Methods and systems for lowering blood pressure through reduction of ventricle filling

ABSTRACT

Systems and methods for reducing ventricle filling volume are disclosed. In some embodiments, a stimulation circuit may be used to stimulate a patient&#39;s heart to reduce ventricle filling volume or even blood pressure. When the heart is stimulated at a consistent rate to reduce blood pressure, the cardiovascular system may over time adapt to the stimulation and revert back to the higher blood pressure. In some embodiments, the stimulation pattern may be configured to be inconsistent such that the adaptation response of the heart is reduced or even prevented. In some embodiments, a stimulation circuit may be used to stimulate a patient&#39;s heart to cause at least a portion of an atrial contraction to occur while the atrioventricular valve is closed. Such an atrial contraction may deposit less blood into the corresponding ventricle than when the atrioventricular valve is opened throughout an atrial contraction.

This application is a continuation of U.S. application Ser. No.15/911,249, filed Mar. 5, 2018, now U.S. Pat. No. 10,610,689, issuedApr. 7, 2020, which is a continuation of U.S. application Ser. No.14/652,856, filed Jun. 17, 2015, now U.S. Pat. No. 9,937,351, issuedApr. 10, 2018, which is a U.S. National Stage of InternationalApplication No. PCT/US2013/076600, filed Dec. 19, 2013, which claimspriority to U.S. application Ser. No. 13/826,215, filed Mar. 14, 2013,now U.S. Pat. No. 9,008,769, issued Apr. 14, 2015, and to U.S.Provisional Application No. 61/740,977, filed Dec. 21, 2012, all ofwhich are herein incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

Embodiments of the present invention relate to the field of treatinghypertension through controlling cardiac filling. Specific embodimentsinclude application of focal, electrical stimulation to the heart.

2. Description of Related Art

Variations in blood pressure are known to occur normally, due forexample to increased activity (which normally elevates blood pressure)or significant blood loss (which tends to cause a reduction in bloodpressure). Blood pressure is however normally maintained within alimited range due for example to the body's baroreflex, whereby elevatedor decreased blood pressure affects cardiac function and thecharacteristics of the cardiovascular system by a feedback loop. Suchfeedback control is mediated by the nervous system as well as by theendocrine system (e.g., by natriuretic peptide). In hypertensiveindividuals, while baroreflex does function, blood pressure ismaintained at an elevated level.

Hypertension, or high blood pressure (e.g., blood pressure of 140/90mmHg or higher), is a serious health problem affecting many people. Forexample, approximately 74.5 million people aged 20 years and older andliving in the United States have high blood pressure. Hypertension maylead to such life-threatening conditions as stroke, heart attack, and/orcongestive heart failure. Approximately 44.1% of people with high bloodpressure and under current treatment have satisfactory control of theirhypertension. Correspondingly, 55.9% of the same people have poorcontrol. Traditionally, treatment for hypertension has includedmedication and lifestyle changes. These two types of treatment are noteffective for all patients. Additionally, side effects may preventcertain patients from taking medication. Accordingly, there remains aneed for additional techniques for lowering blood pressure.

SUMMARY OF THE INVENTION

Methods and devices for reducing blood pressure are disclosed. Someembodiments treat hypertension mechanically instead of or in addition totreating hypertension pharmaceutically. In some embodiments, anelectrical stimulator, such as a pacemaker or other type of devicehaving a pulse generator, may be used to stimulate a patient's heart toreduce blood pressure. When the heart is stimulated in a consistent wayto reduce blood pressure, the cardiovascular system may adapt to thestimulation over time and revert to a higher blood pressure. Therefore,in some embodiments, the stimulation pattern may be configured to beable to modulate the baroreflex such that the adaptation response of thecardiovascular system is reduced or even prevented.

In some embodiments, an electrical stimulator may be used to stimulate apatient's heart to cause at least a portion of an atrial contraction tooccur while the atrioventricular valve is closed. Such an atrialcontraction may deposit less blood into the corresponding ventricle thanwhen the atrioventricular valve is opened during an atrial contraction.

Some embodiments may use artificial valves in treating hypertension. Insome medical conditions, where one or more of the atrioventricular (AV)valves malfunctions, the valve(s) may be replaced by implantation ofartificial (prosthetic) valve(s). These artificial valves may benormally configured to passively open and close, as do natural valves,as a function of pressure differences between the atria and ventricles.Passive artificial valves are normally classified in three types basedon their mechanical structure: caged ball valves, tilting disc valves,and bi-leaflet valves. As an alternative, some embodiments may use anactive artificial valve that is configured to actively open and close.

In one aspect, an embodiment provides a system for reducing bloodpressure in a patient having a pretreatment blood pressure. The systemmay comprise at least one stimulation electrode for stimulating at leastone chamber of a heart of a patient with a stimulating pulse. The systemmay comprise at least one controller configured to execute a stimulationpattern of stimulating pulses to at least a chamber of the heart. Thestimulation pattern may include a first stimulation setting and a secondstimulation setting different from the first stimulation setting. Atleast one of the first stimulation setting and the second stimulationsetting may be configured to reduce or prevent atrial kick.

In one aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient. The system mayinclude at least one controller configured to execute a stimulationpattern comprising multiple stimulation pulses. At least one stimulationpulse of the multiple stimulation pulses may have a first stimulationsetting configured to reduce atrial kick in at least one ventricle. Atleast one stimulation pulse of the multiple stimulation pulses may havea second stimulation setting configured to reduce the baroreflexresponse to the reduction in atrial kick such that the increase in bloodpressure values occurring between stimulation pulses is limited to apredetermined value or range of values.

In another aspect, an embodiment provides a device for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The device may comprise astimulation circuit configured to deliver a stimulation pulse to atleast one of an atrium and a ventricle. The device may comprise aprocessor circuit coupled to the stimulation circuit and optionally alsoto a sensing circuit.

In some embodiments, the device processor circuit may be configured tooperate in an operating mode in which the device controls the AV delay,which, as used herein, may be taken to mean a delay occurring in asingle heartbeat between ventricle excitation and/or contraction andatrial excitation and/or contraction. In addition, as used herein, theAV delay in a system or method may be taken to mean, within oneheartbeat, a time delay between delivery of at least one excitatorystimulus to a ventricle and one of: the sensing of an onset of atrialexcitation; the timing of an anticipated onset of atrial excitation; andthe delivery of at least one excitatory stimulus to the atrium.

This AV delay may be set by delivering at least one stimulation pulse toboth of at least one atrium and at least one ventricle. Optionally thisstimulation is performed at a rate that is higher than the naturalactivity of the heart. Such rate may, for example, be set using at leastone sensing electrode to sense the natural activity in the heart (e.g.,in the right atrium) and adjusting the stimulation pulse delivery rateaccordingly.

Optionally, when ventricular excitation is timed to commence before thedelivery of one or more stimulation pulses to the atria, the delivery ofstimulation pulses to the heart is timed such that one or moreexcitatory pulses are delivered to an atrium at a time that is earlierthan the next anticipated natural onset of atrial excitation.

In some embodiments, the AV delay may be set by delivering at least onestimulation pulse to one or more ventricles but not to the atria. Insuch case, the natural activity of one or more of the atria may besensed and the timing of ventricle excitation and/or contraction may beset to precede its natural expected timing based on the sensed atrialactivity rate.

In some embodiments, the processor circuit may be configured to operatein an operating mode in which a ventricle is stimulated to causeventricular excitation to commence between about 0 milliseconds (ms) andabout 50 ms before the onset of atrial excitation in at least oneatrium, thereby reducing the ventricular filling volume from thepretreatment ventricular filling volume and reducing the patients bloodpressure from the pretreatment blood pressure. In such embodiments,atrial excitation may be sensed to determine the onset of atrialexcitation. For example, the processor circuit may be configured tooperate in an operating mode in which one or more excitatory pulses aredelivered to a ventricle between about 0 ms and about 50 ms before anext atrial excitation is anticipated to take place. The time intervalbetween the onset of atrial excitation and the moment that atrialexcitation is sensed may be known or estimated, and used to calculatethe timing of an onset of atrial excitation. For example, if it is knownor estimated that atrial excitation is sensed 5 ms after the onset ofatrial excitation and the ventricle is to be stimulated 20 ms before theonset of atrial excitation, then the ventricle is to be stimulated 25 msbefore the next anticipated sensing of atrial excitation. In otherembodiments, the processor circuit may be configured to operate in anoperating mode in which an atrium is stimulated to cause atrialexcitation to commence between about 0 ms and about 50 ms after theonset of ventricular excitation in at least one ventricle, therebyreducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. For example, the processor circuitmay be configured to operate in an operating mode in which one or moreexcitatory pulses are delivered to an atrium between about 0 ms andabout 50 ms after one or more excitatory pulses are provided to thepatient's ventricle. In such embodiments, the pacing may be timedwithout relying on sensing atrial excitation. Optionally, in suchembodiments, atrial excitation is sensed in order to confirm that one ormore excitatory pulses are delivered to an atrium before a naturalexcitation takes place. Optionally, atrial excitation is set to commencebetween about 0 ms and about 50 ms after the onset of ventricularexcitation when the intrinsic atrial excitation rate is lower than theintrinsic ventricular excitation rate.

In some embodiments, the timing of the mechanical contraction inrelation to electrical excitation of a chamber for a patient may bedetermined, for example, by sensing changes in atrial and ventricularpressures, sensing wall motion using ultrasound (e.g., echocardiographyor cardiac echo), changes in impedance, or the opening and/or closing ofa cardiac valve, using implanted and/or external sensors as known in theart. Examples for such sensors include pressure sensors, impedance,ultrasound sensors, and/or one or more audio sensors and/or one or moreblood flow sensors.

The timing of the mechanical contraction in relation to electricalexcitation of a chamber for a patient may be taken into account and theprocessor circuit may be configured accordingly, such that the one ormore excitatory pulses are delivered to the heart in a timing that willgenerate a desired pattern of contraction. This may be performed in aclosed loop mode, using one or more implanted sensors, and/or may beperformed occasionally (e.g., on implantation of a device and/or duringa checkup), for example, using an interface with an external measurementdevice.

The operating mode may include stimulating the ventricle to cause theventricle to commence contraction before the onset of contraction of theat least one atrium.

The operating mode may include stimulating the ventricle to cause theventricle to commence contraction before the end of contraction of theat least one atrium, thereby causing the AV valve to be closed during atleast part of a contraction of the at least one atrium.

The operating mode may include stimulating the ventricle to cause theventricle to commence contraction within less than 100 ms after theonset of contraction of the at least one atrium.

Optionally, care is taken to ensure that atrial contraction willcommence before ventricle contraction has reached peak pressure. This ispossible even in cases in which ventricular contraction will havecommenced before the onset of atrial contraction, as atrial contractionis typically faster than ventricular contraction. Accordingly, one ofthe following settings may be selected:

-   -   a. The operating mode may include stimulating the ventricle to        cause the ventricle to commence contraction at any time during        atrial contraction but before the atrium reaches its maximal        contraction force.    -   b. The operating mode may include stimulating the ventricle to        cause the ventricle to commence contraction at any time during        atrial contraction but after the atrium reaches its maximal        contraction force.    -   c. The operating mode may include stimulating the ventricle at        such timing that contraction would commence in both the atrium        and ventricle at essentially the same time (e.g., with no more        than 5 ms from one another),    -   d. The operating mode may include stimulating the ventricle to        cause the ventricle to commence contraction at such timing that        the peak of atrial contraction would occur when the ventricle is        at maximal stretch, thus causing an increase in the stretch of        the atrial wall.

The operating mode may include stimulating the ventricle to cause theventricle to contract at least partially before the onset of contractionof the at least one atrium, thereby causing the AV valve to be closedduring the onset of contraction of the at least one atrium.

Optionally, the processor circuit may be configured to operate in anoperating mode in which one or more excitatory pulses are delivered toan atrium between about 0 ms and about 50 ms after one or moreexcitatory pulses are delivered to the patient's ventricle.

In another aspect, an embodiment provides a method for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The method may comprisedelivering a stimulation pulse from a stimulation circuit to at leastone of an atrium and a ventricle, and operating a processor circuitcoupled to the stimulation circuit to operate in an operating mode inwhich a ventricle is stimulated to cause ventricular excitation tocommence between about 0 ms and about 50 ms before the onset of atrialexcitation in at least one atrium, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume andreducing the patient's blood pressure from the pretreatment bloodpressure. In such embodiments, atrial excitation may be sensed todetermine the onset of atrial excitation. For example, the method mayinclude delivering one or more excitatory pulses to a ventricle betweenabout 0 ms and about 50 ms before a next atrial excitation isanticipated to take place. The time interval between the onset of atrialexcitation and the moment that atrial excitation is sensed may be knownand used to calculate the timing of the onset of atrial excitation. Forexample, if it is known or estimated that atrial excitation is sensed 5ms after the onset of atrial excitation and the ventricle is to bestimulated 20 ms before the onset of atrial excitation, then theventricle is to be stimulated 25 ms before the next anticipated sensingof atrial excitation. In other embodiments, the method may compriseoperating a processor circuit coupled to the stimulation circuit tooperate in an operating mode in which an atrium is stimulated to causeatrial excitation to commence between about 0 ms and about 50 ms afterthe onset of ventricular excitation in at least one ventricle, therebyreducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. For example, the method mayinclude delivering one or more excitatory pulses to an atrium betweenabout 0 ms and about 50 ms after delivering one or more excitatorypulses to the patient's ventricle. In such embodiments, the pacing maybe timed without relying on sensing atrial excitation. Optionally, suchembodiments comprise sensing atrial excitation in order to confirm thatone or more excitatory pulses are delivered to an atrium before anatural excitation takes place. Optionally, atrial excitation is set tocommence between about 0 ms and about 50 ms after the onset ofventricular excitation when the intrinsic atrial excitation rate islower than the intrinsic ventricular excitation rate.

In some embodiments, the timing of the mechanical contraction inrelation to electrical excitation of a chamber for a patient may beevaluated using, for example, ultrasound (e.g., echocardiography orcardiac echo) or other known means. The timing of the mechanicalcontraction in relation to electrical excitation of a chamber for apatient may be taken into account and the timing of the delivery of theone or more excitatory pulses to the heart may be selected so as togenerate a desired pattern of contraction.

The operating mode may include stimulating the ventricle to cause theventricle to contract before the onset of contraction of the at leastone atrium.

The operating mode may include stimulating the ventricle to cause theventricle to contract before the onset of contraction of the at leastone atrium, thereby causing the AV valve to be closed during at leastpart of a contraction of the at least one atrium.

The operating mode may include stimulating the ventricle to cause theventricle to contract before the end of contraction of the at least oneatrium, thereby causing the AV valve to be closed during the onset ofcontraction of at least atrium.

Optionally, the method comprises delivering one or more excitatorypulses to an atrium between about 0 ms and about 50 ms after deliveringone or more excitatory pulses to the patient's ventricle.

In another aspect, an embodiment provides a device for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The device may comprise astimulation circuit configured to deliver a stimulation pulse to atleast one cardiac chamber of a patient's heart. The device may comprisea processor circuit coupled to the stimulation circuit. The processorcircuit may be configured to operate in an operating mode in which atleast one cardiac chamber is stimulated to cause between about 40% of anatrial contraction and about 100% of an atrial contraction to occur at atime when an atrioventricular valve related to the atrium is closed,thereby reducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. This can be achieved, for example,by causing the atrium to commence contraction about 60 ms or less beforethe closure of the AV valve. Optionally, this timing may be setperiodically (e.g., upon implantation) based on data from an externalsensor and/or as a closed loop using one or more implanted sensors.

In another aspect, an embodiment provides a device for reducing bloodpressure of a patient having a pretreatment blood pressure and apretreatment ventricular filling volume. The device may comprise astimulation circuit configured to deliver a stimulation pulse to atleast one cardiac chamber. The device may comprise a processor circuitcoupled to the stimulation circuit. The processor circuit may beconfigured to operate in an operating mode in which at least one cardiacchamber is paced to cause about 50% to about 95% of an atrialcontraction to occur during ventricular systole, thereby reducing theventricular filling volume from the pretreatment ventricular fillingvolume and reducing the patient's blood pressure from the pretreatmentblood pressure. This can be achieved, for example, by causing the atriumto commence contraction about 50 ms to 5 ms before commencement ofventricular contraction. Optionally, the timing of commencement ofventricular contraction may be set according to the timing of closure ofan AV valve. Optionally, this timing may be set periodically (e.g., uponimplantation) based on data from an external sensor and/or as a closedloop using one or more implanted sensors.

In another aspect, an embodiment provides a method, carried out with animplanted heart muscle stimulator associated with a heart of a patient,for treating a blood pressure disorder in the patient, the patienthaving a pretreatment blood pressure. The method may comprisestimulating a heart to cause an atrium thereof to contract while a heartvalve associated with the atrium is closed such that the contractiondistends the atrium, and the distending atrium results in reducing thepatient's blood pressure from the pretreatment blood pressure. This canbe achieved, for example, by causing the atria to contract at a timewhen the pressure in the ventricle is maximal so that the active forceof atrial contraction will increase atrial stretch above the maximalpassive stretch caused by the contraction of the associatedventricle(s). In such cases, the timing of the maximal contraction ofthe atria should coincide with the end of the isovolumic period orduring the rapid ejection period of the ventricle. Optionally, thistiming may be set periodically (e.g., upon implantation) based on datafrom an external sensor and/or as a closed loop using one or moreimplanted sensors.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient with astimulation pattern comprising at least one stimulation pulse. Thesystem may include at least one controller configured to receive inputrelating to the patient's blood pressure and adjust the stimulationpattern based on said blood pressure. For example, the input may includereceiving data sensed by one or more sensors (implanted or external)and/or receiving data provided by a user. For example, duringimplantation and/or periodic checks, a user may provide data regardingmeasured blood pressure. Optionally, the system includes an input portfor receiving this input by wired and/or wireless communication from ameasuring sensor and/or a user interface. The input may comprise datarelating to blood pressure (BP) or a change in BP, which may be measuredas systolic BP (SysBP), diastolic BP, mean arterial BP, and/or any otherrelated BP parameter. For example, at least one sensor may sense thepressure or changes of pressure in one or more cardiac chambers andadjust the stimulation pattern based on the pressure or changes inpressure. In another embodiment, the sensor may sense the pressure inmore than one chamber and adjust the stimulation based on the relationbetween the pressure waveforms of the two chambers.

The controller may be configured to adjust the stimulation pattern byperforming an adjustment process that includes adjusting a parameter ofa first stimulation setting of at least one of the at least onestimulation pulse.

The first stimulation setting may be configured to reduce or preventatrial kick in at least one ventricle.

The parameter may include the adjustment of the AV delay. For example, anatural AV delay may be a range of 120 to 200 ms between the onset ofatrial excitation and the onset of ventricular excitation, whetheroccurring naturally (i.e., without the delivery of a stimulus to theheart) or by setting the timing of the delivery of stimuli to one ormore of the atrium and ventricle. Optionally, adjusting the AV delaymeans adjusting it from a normal AV delay (of, for example, 120 ms) to ashorter AV delay (for example, 0 to 70 ms from the onset of atrialexcitation to onset of ventricular excitation; or an AV delay of 0 to−50 ms in which the ventricular excitation occurs before atrialexcitation). In a preferred embodiment of the invention, a stimulationsetting having an AV delay of between −50 ms to 70 ms, preferably −40 msto 60 ms, more preferably −50 ms to 0 or 0 to 70 ms, preferably >0 to 70ms, is chosen to reduce or prevent atrial kick.

The stimulation pattern may be configured to cause a reduction in bloodpressure by at least a predetermined amount within about 3 sec from anapplication of electricity to the heart, and to maintain a reduction inblood pressure for a time interval of at least 1 minute. For example, astimulation pattern may be selected and/or adjusted based on feedbackrelating to one or more sensed BP parameters.

The time interval may be at least 5 minutes.

The predetermined amount of blood pressure reduction may be 8 mmHg ormore.

The predetermined amount of blood pressure reduction may be at least 4%of the patient's pretreatment blood pressure.

The patient's blood pressure may not exceed a predetermined averagevalue during the time interval by more than a predetermined degree.

The predetermined degree may be a difference of about 8 mmHg or less.

The controller may be configured to execute a plurality of stimulationpatterns and receive for each of the stimulation patterns acorresponding input data relating to the patient's blood pressure duringthe stimulation. The controller may be configured to calculate for eachof the plurality of stimulation patterns at least one blood pressurevariation parameter relating to the input data. The controller may beconfigured to adjust the stimulation pattern according to the bloodpressure variation parameter.

The controller may be configured to adjust the stimulation pattern to bethe one with the best blood pressure variation parameter.

The best blood pressure variation parameter may be one that displays thelowest degree of baroreflex, or the lowest degree or rate of adaptationas detailed herein

The best blood pressure variation parameter may be one that displays abaroreflex or degree of adaptation within a predetermined range asdetailed herein.

The at least two stimulation patterns of the plurality of stimulationpatterns may each comprise at least one stimulation pulse having astimulation setting configured to reduce or prevent atrial kick in atleast one ventricle. The at least two stimulation patterns may differone from another by the number of times or the length of time the atleast one stimulation pulse is provided in sequence.

The plurality of stimulation patterns may differ by the number of timesor the length of time that the system is configured to elicit apredetermined AV delay in sequence.

The at least two stimulation patterns of the plurality of stimulationpatterns may differ from another by one or more stimulation settingsincluded within each of the at least two stimulation patterns.

The plurality of stimulation patterns may include a first stimulationpattern and a second stimulation pattern executed after the firststimulation pattern. The second stimulation pattern may have at leastone stimulation setting that was set based on an algorithm using bloodpressure variation parameters relating to the input data of the firststimulation pattern.

The system may comprise a blood pressure sensor for providing the inputdata relating to the patient's blood pressure.

The blood pressure sensor may be implantable.

The blood pressure sensor and the controller may be configured tooperate at least partially as a closed loop.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient with astimulation pulse. The system may comprise a controller. The controllermay be configured to provide a first stimulation pattern comprising atleast one stimulation setting configured to reduce or prevent atrialkick in at least one ventricle for a first time interval and to receivea first input data relating to a patient's blood pressure during saidfirst time interval. The controller may be configured to calculate atleast one blood pressure variation parameter relating to the first inputdata. The controller may be configured to adjust at least one parameterof a second stimulation pattern comprising a second stimulation settingconfigured to reduce or prevent atrial kick in at least one ventricle.The second stimulation setting may be based upon the at least one bloodpressure variation parameter. The controller may be configured toprovide the second stimulation pattern for a second time interval.

In another aspect, an embodiment may provide a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient with astimulation pulse. The system may comprise at least one controllerconfigured to execute a stimulation pattern comprising at least onestimulation setting configured to reduce or prevent atrial kick in atleast one ventricle. The stimulation pattern may be selected to cause animmediate reduction in blood pressure from an initial pressure value toa reduced pressure value and to maintain a patient's average bloodpressure at rest at least 8 mmHg below the initial pressure.

The reduced blood pressure value may be maintained for a time intervalof at least 1 minute.

In another aspect, an embodiment provides a kit for reducing bloodpressure. The kit may comprise at least one device for setting astimulation pattern for reducing blood pressure. The device may compriseat least one stimulation electrode. The device may comprise a controllerfor setting an adjustable stimulation pattern and a set of instructionsfor adjusting the stimulation pattern based on input relating to patientblood pressure.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient. The system maycomprise at least one controller configured to execute a stimulationpattern comprising at least one stimulation pulse having at least onestimulation setting configured to reduce or prevent atrial kick in atleast one ventricle. The at least one stimulation setting may beconfigured such that maximum atrial stretch is at a value that is aboutequal to or lower than the maximum atrial stretch of the same heart whennot receiving stimulation. Atrial stretch may be measured, calculated,and/or estimated as known in the art. In some embodiments, atrialstretch determination may include measuring atrial pressure. In someembodiments, atrial stretch determination may include measuring orestimating the dimension of an atrium (e.g., diameter, size, orcircumference).

The at least one stimulation setting may be configured to cause anatrium to be at maximum contraction when the AV valve is open.

The at least one stimulation setting may be configured to alter themechanics of at least one atrial contraction such that the mechanics ofthe at least one atrial contraction are different from the mechanics ofa previous natural atrial contraction. The mechanics of atrialcontraction may be assessed using any known technique including, forexample, ultrasound (e.g., echocardiography or cardiac echo).

The at least one stimulation setting may be configured to reduce theforce of at least one atrial contraction. The force of atrialcontraction may be reduced, for example, by temporarily generatingatrial spasm or atrial flutter. One example is the delivery of a burstof rapid stimulation pulses to the atrium for a short period ofpredefined time. The force of atrial contraction can be calculated fromsensing of atrial pressure and/or a derivative thereof such as wallmotion or flow using any known means. Such sensing may be used as afeedback in a closed loop and/or occasionally (e.g., upon implantationand/or checkups).

The at least one stimulation setting may be configured to prevent atleast one atrial contraction. Atrial contraction may be prevented, forexample, by temporarily generating atrial spasm or atrial flutter. Oneexample is the delivery of a burst of rapid stimulation pulses to theatrium for a short period of predefined time.

In another aspect, an embodiment provides a system for reducing bloodpressure. The system may comprise at least one stimulation electrode forstimulating at least one chamber of a heart of a patient. The at leastone controller may be configured to execute a stimulation pattern ofstimulation pulses to the heart of a patient. The at least onecontroller may be configured to receive input relating to the patient'sAV valve status. This input may be provided by wired or wirelesscommunication from an implanted or external acoustic sensor or bloodflow sensor and/or via a user interface. The at least one controller maybe configured to adjust the at least one stimulation pattern based onsaid valve status.

The input relating to the patient's AV valve status may be indicative ofthe timing of closure of the AV valve.

The input relating to the patients AV valve status may be provided basedon a heart sound sensor.

The input relating to the patient's AV valve status may be providedbased on a blood flow sensor.

The blood flow sensor may include an implanted sensor.

The blood flow sensor may include an ultrasound sensor for sensing bloodflow through the AV valve.

The blood flow sensor and the controller may be configured to operate atleast partially as a closed loop.

The stimulation pattern may comprise at least one stimulation pulseconfigured to reduce or prevent the atrial kick in at least oneventricle.

The step of adjusting the at least one stimulation pattern may includeadjusting the AV delay of at least one stimulation pulse.

In another aspect, an embodiment provides a system for reducingventricular filling volume in a patient having a pretreatmentventricular filling volume. The system may comprise a stimulationcircuit configured to deliver a stimulation pulse to at least onecardiac chamber. The system may comprise at least one controllerconfigured to execute the delivery of one or more stimulation patternsof stimulation pulses to at least one cardiac chamber. At least one ofthe stimulation pulses may have a first stimulation setting and at leastone of the stimulation pulses may have a second stimulation settingdifferent from the first stimulation setting. At least one of the firststimulation setting and the second stimulation setting may be configuredto reduce or prevent atrial kick, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume.

The first stimulation setting and the second stimulation setting may beconfigured to reduce or prevent atrial kick.

The first stimulation setting may have a different AV delay than the AVdelay of the second stimulation setting.

At least one of the one or more stimulation patterns may be repeated atleast twice in a period of one hour.

The at least one controller may be configured to execute the one or morestimulation patterns consecutively for a time interval lasting 10minutes or longer. The first stimulation setting may be configured toreduce or prevent atrial kick in at least one ventricle for at least 50%of the time interval.

The second stimulation setting may have a longer AV delay than the firststimulation setting.

The second stimulation setting has a longer AV delay than the firststimulation setting.

The one or more consecutive stimulation patterns may comprise at leastone stimulation pulse having the first stimulation setting for at leastabout 85% of the time interval.

The time interval may be at least 30 minutes long.

The time interval may be at least one hour long.

The time interval may be at least 24 hours long.

The one or more consecutive stimulation patterns may comprise at leastone stimulation pulse having a third stimulation setting different fromthe first stimulation setting and the second stimulation setting andconfigured to reduce or prevent atrial kick in at least one ventricle.

The one or more consecutive stimulation patterns may comprise at leastone stimulation pulse having a third stimulation setting different fromthe first stimulation setting and the second stimulation setting andconfigured not to reduce or prevent atrial kick in at least oneventricle for less than about 50% of the time interval.

The one or more consecutive stimulation patterns may comprise a thirdstimulation configured not to reduce or prevent atrial kick in at leastone ventricle for about 20% or less of the time interval.

The one or more stimulation patterns may comprise a sequence of 10-60stimulation pulses having the first stimulation setting. The firststimulation setting may be configured to reduce or prevent atrial kickin at least one ventricle, and a sequence of 1-10 heartbeats embeddedwithin the 10-60 stimulation pulses. The sequence of 1-10 heartbeats mayhave a longer AV delay than the first stimulation setting.

The sequence of 1-10 heartbeats may include at least one stimulationpulse having a first stimulation setting configured to reduce or preventatrial kick in at least one ventricle.

The sequence of 1-10 heartbeats may include at least one stimulationpulse having a second stimulation setting.

The sequence of 1-10 heartbeats may include a natural AV delay.

At least one heartbeat of the sequence of 1-10 heartbeats may occurwithout stimulation.

The first stimulation setting may be configured to reduce atrial kick inat least one ventricle and the second stimulation setting may beconfigured to reduce the baroreflex response or adaptation to thereduction in atrial kick such that the increase in blood pressure valuesoccurring between stimulation pulses is limited to a predeterminedvalue.

The second stimulation setting may be configured to allow an increase inblood pressure for about 1 heartbeat to 5 heartbeats.

The stimulation pattern may include multiple stimulation pulses havingthe first stimulation setting,

The stimulation pattern may include multiple stimulation pulses havingthe second stimulation setting.

Between about 1% of the multiple stimulation pulses and 40% of themultiple stimulation pulses of the stimulation pattern may have thesecond stimulation setting.

The stimulation pattern may include a ratio of stimulation pulses havingthe first stimulation setting to the stimulation pulses having thesecond stimulation setting that corresponds to a ratio of time constantsof a response to increase and decrease in blood pressure.

The first stimulation setting may include a first AV delay and thesecond stimulation setting may include a second AV delay. The first AVdelay may be shorter than the second AV delay.

The stimulation pattern may include multiple stimulation pulses havingthe first stimulation setting.

The stimulation pattern may include multiple stimulation pulses havingthe second stimulation setting.

Between about 1% of the multiple stimulation pulses and 40% of themultiple stimulation pulses of the stimulation pattern may have thesecond stimulation setting.

The stimulation pattern may include a ratio of stimulation pulses havingthe first stimulation setting to the stimulation pulses having thesecond stimulation setting that corresponds to a ratio of time constantsof the response to increase and decrease in blood pressure.

The stimulation pattern may include a ratio of about 8 to about 13stimulation pulses having the first stimulation setting to about 2 toabout 5 the stimulation pulses having the second stimulation setting.

One of the first stimulation setting and the second stimulation settingmay be configured to invoke a hormonal response from the patient's body.

In another aspect, an embodiment provides a system for reducingventricular filling volume of a patient having a pretreatmentventricular filling volume. The system may comprise a stimulationcircuit configured to deliver a stimulation pulse to at least onecardiac chamber. The system may comprise at least one controllerconfigured to execute the delivery of one or more stimulation patternsof stimulation pulses to at least one cardiac chamber. At least one ofthe stimulation pulses may include a setting configured to cause aventricular excitation to commence between about 0 ms and about 70 msafter the onset of atrial excitation, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume. Forexample, the processor circuit may be configured to operate in anoperating mode in which one or more excitatory pulses are delivered tothe ventricle between about 0 ms and about 70 ms after the onset ofatrial excitation in at least one atrium occurs, or between about 0 msand about 70 ms after one or more excitatory pulses are delivered to theatrium.

In some embodiments, the timing of a sensed atrial excitation may bedetermined by taking into account a delay between actual onset ofexcitation and the sensing thereof. For example, if a sensing delay isestimated to be 20-40 ms, and stimulation pulses are to be delivered0-70 ms after onset of atrial excitation, a system may be set to deliverpulses between 40 ms before the next anticipated sensing event to 30 msafter the next anticipated sensing event or 30 ms after the next sensingevent. Likewise, if the stimulation pulses are to be delivered to theventricle 0-50 ms before onset of atrial excitation, assuming the same20-40 ms sensing delay, a system may be set to deliver pulses between 40ms before the next anticipated sensing event to 90 ms before the nextanticipated sensing event. Sensing delays may be due to one or more of adistance between the site of onset of excitation and a sensingelectrode, the level of the electrical signal, characteristics of thesensing circuit, and the threshold set of a sensing event. The delay mayinclude, for example, the duration of the signal propagation from theorigin of excitation to the electrode location, the duration related tothe frequency response of the sensing circuit, and/or the durationnecessary for the signal propagation energy to reach a level detectableby a sensing circuit. The delay may be significant and can range, forexample, between about 5 ms to about 100 ms. One approach for estimatingthe delay is to use the time difference between an AV delay measuredwhen both atrium and ventricle are sensed and the AV delay when theatrium is paced and the ventricle is sensed. Other approaches may usecalculation of the amplifier response time based on the set threshold,signal strength, and frequency content. Other approaches may includemodifying the delay used with atrial sensing until the effect on bloodpressure is the same as the effect obtained by pacing both atrium andventricle with the desired AV delay.

In another aspect, a system is provided for reducing ventricular fillingvolume in a patient having a pretreatment ventricular filling volume.The system may include a stimulation circuit configured to deliver astimulation pulse to at least one cardiac chamber. At least onecontroller may be configured to execute the delivery of one or morestimulation patterns of stimulation pulses to at least one cardiacchamber for a time interval lasting 10 minutes or longer. At least oneof the stimulation pulses may have a first stimulation settingconfigured to reduce or prevent atrial kick in at least one ventriclefor at least 5 minutes of the time interval and at least one of thestimulation pulses has a second stimulation setting different from thefirst stimulation setting, thereby reducing the ventricular fillingvolume from the pretreatment ventricular filling volume.

In another aspect, a method is provided for reducing ventricular fillingin a patient having a pretreatment ventricular filling volume. Themethod may include a step of delivering one or more stimulation patternsof stimulation pulses to at least one cardiac chamber for a timeinterval lasting 10 minutes or longer. At least one of the stimulationpulses may have a first stimulation setting configured to reduce orprevent atrial kick in at least one ventricle for at least 5 minutes ofthe time interval and at least one of the stimulation pulses has asecond stimulation setting different from the first stimulation setting.

Other systems, methods, features, and advantages of the invention willbe, or will become, apparent to one of ordinary skill in the art uponexamination of the following figures and detailed description. It isintended that all such additional systems, methods, features andadvantages be included within this description and this summary, bewithin the scope of the invention, and be protected by the followingclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention can be better understood with reference to the followingdrawings and description. The components in the figures are notnecessarily to scale, emphasis instead being placed upon illustratingthe principles of the invention. Moreover, in the figures, likereference numerals designate corresponding parts throughout thedifferent views.

FIG. 1 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 2 shows an enlarged view of the portion of FIG. 1 marked by dashedrectangle A;

FIG. 3A depicts an enlarged view of the portion of FIG. 2 between timepoint a and point a′;

FIG. 3B depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle A′;

FIG. 4 depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle B;

FIG. 5A depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle C;

FIG. 5B depicts an enlarged view of the portion of FIG. 5A between timepoint c and point c′;

FIG. 6 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 7 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time;

FIG. 8 is a flow chart showing an exemplary method for setting and/orselecting a stimulation pattern;

FIG. 9 is a schematic diagram illustrating an exemplary system forreducing blood pressure;

FIG. 10A shows a time plot including: electrocardiogram, aortic pressureand left ventricular pressure of a healthy canine heart;

FIG. 10B shows a time plot including: electrocardiogram, aortic pressureand left ventricular pressure of a healthy canine heart;

FIG. 11A shows a time plot of a hypertensive canine heart, includingright atria pressure, magnified diastolic portion of right ventricularpressure, right ventricular pressure and electrocardiogram;

FIG. 11B shows a time plot of a hypertensive canine heart, includingright atria pressure, magnified diastolic portion of right ventricularpressure, right ventricular pressure and electrocardiogram;

FIG. 12 shows a right atria pressure, magnified diastolic portion ofright ventricular pressure, right ventricular pressure, left ventricularpressure and at the same graph aortic pressure and an electrocardiogramof a hypertensive canine heart;

FIG. 13 is a flow chart showing an exemplary method 40 for reducingblood pressure;

FIG. 14 is a flow chart showing an exemplary method 40 for reducingblood pressure;

FIG. 15 is a schematic diagram illustrating an artificial valveaccording to an embodiment; and

FIG. 16 shows the systolic blood pressure of a hypertensive patientreceiving a stimulation signal, plotted against time.

DETAILED DESCRIPTION

The human heart comprises two atria and two ventricles. In a normalheart cycle, cardiac contraction begins with atrial contraction, whichis followed by contraction of the ventricles.

The mechanical process of cardiac contraction is controlled byconduction of electricity in the heart. During each heartbeat, a wave ofdepolarization is triggered by cells in the sinoatrial node. Thedepolarization propagates in the atria to the atrioventricular (AV) nodeand then to the ventricles. In a healthy heart, atrioventricular delay(AV delay), i.e., the delay time between the onset of atrial excitationand the onset of ventricular excitation, is normally between 120milliseconds (ms) and 200 ms. The relative timing of the atrialcontraction and the ventricular contraction is affected inter alia bythe relative timing of excitation of each chamber and by the time neededby the chamber to generate mechanical contraction as a result of theelectrical activation (depending on size, speed of propagation,differences in myocyte properties, etc.).

Before contraction, the heart muscle is relaxed and blood flows freelyinto the ventricles from the atria, through a valve between them. Thisperiod can be divided into a rapid filling phase and a slow fillingphase. The rapid filling phase commences just after the relaxation ofthe ventricle, during which blood from the venous system and the atriarapidly fills the ventricle. The rapid filling phase lasts forapproximately 110 ms and is followed by the slow filling phase, whichlasts until the start of the contraction of the atria. The duration ofthe slow filling phase depends on the heart rate. Thereafter, as anatrium contracts, pressure increases in the atrium and causes blood toflow more rapidly into the ventricle. This contribution of atrialcontraction to ventricle filling is known as the “atrial kick.” Atrialkick is normally responsible for about 10%-30% of ventricle filling.

A cardiac cycle begins at the onset of atrial excitation. Then, about50-70 ms thereafter the atrium begins to contract, for a period of about70-110 ms. Meanwhile, the electrical stimulus propagates to theventricle and the onset of ventricle excitation occurs at an AV delay ofabout 120-200 ms later (the AV delay can be about 250 ms in someunhealthy individuals). As the ventricle contracts, pressure builds upwithin it and passively closes the valves between each of the atria anda respective ventricle (AV valves), thus stopping the flow of blood fromthe atrium into the ventricle and preventing backflow. During the nextperiod of the contraction, a period known as isovolumic contraction thatlasts approximately 50 ms, all ventricle valves are closed and thepressure in the ventricle rapidly rises with no significant change involume. As ventricular pressure further increases, the valve between theventricle and artery opens and blood flows out of the ventricle and awayfrom the heart. The contraction is further divided into a rapid ejectionperiod and a decreased ejection period. The rapid ejection period lastsapproximately 90-110 ms, during which about ⅔ of the stroke volume isejected. At the end of the rapid ejection period, the pressure in theventricle and the atria reaches its peak. The rapid ejection period isfollowed by the decreased ejection period lasting about 130-140 ms.Thereafter, all valves close again and the ventricle relaxes inisovolumic relaxation for about 60-80 ms, during which the pressure inthe ventricle drops. At this time, the valves between the ventricle andthe atria reopen allowing blood to flow freely into the ventricle, and anew excitation cycle may commence.

In the present disclosure, cardiac stimulation may be used to reduceventricular filling volume and/or blood pressure (BP). BP or a change inBP may be measured as systolic BP (SysBP), diastolic BP, mean arterialBP, BP in one or more chambers, and/or any other related BP parameter.In some embodiments, an electrical stimulator, such as a pacemaker orother type of device having a pulse generator, may be used to stimulatea patient's heart to reduce blood pressure. Electrodes electricallyconnected to the electrical stimulator with a wired or wirelessconnection may be placed adjacent a cardiac chamber. The electricalstimulator may be operated to deliver a pulse to the cardiac chamber viathe electrode.

In some embodiments, stimulating the heart such that the contribution ofatrial contraction to the filling of the ventricles (atrial kick) isreduced or even prevented, reduces cardiac filling at the end ofdiastole and consequently reduces blood pressure. For simplicity, in thefollowing description, such stimulation will be termed “BPR (BloodPressure Reducing) stimulation.” BPR stimulation may include deliveringat least one stimulation pulse to at least a chamber of a heart suchthat atrial kick is reduced or even prevented. Such a pulse will bereferred to herein as a “BPR stimulation pulse” or “BPR pulse” herein.As used herein, a “stimulation pulse” may comprise a sequence of one ormore electrical pulses delivered to one or more chambers of said heartwithin the timeframe of a single heartbeat. For example, in someembodiments, a stimulation pulse may comprise one or more electricalpulses delivered to one or more locations in a ventricle and/or one ormore electrical pulses delivered to one or more locations in an atrium.Thus, in some embodiments, the stimulation pulse may include a firstelectrical pulse delivered to an atrium and a second electrical pulsedelivered to the corresponding ventricle. In some embodiments astimulation pulse may include a single pulse being delivered to aplurality of locations on one or more chambers of the heart.

A stimulation setting means one or more parameters of one or morestimulation pulses delivered in a single cardiac cycle. For example,these parameters may include one or more of: power, a time intervalbetween electrical pulses that are included in a single stimulationpulse (e.g., AV delay), a period of delivery with respect to the naturalrhythm of the heart, the length of a stimulation pulse or a portionthereof, and the site of delivery between two or more chambers and/orwithin a single chamber. A BPR stimulation setting, or “BPR setting,”may include a setting of one or more BPR pulses.

A stimulation pattern may include a series of pulses having identicalstimulation settings or a stimulation pattern may include multiplepulses each having different stimulation settings. For example, astimulation pattern may have one or more pulses having a first settingand one or more pulses having a second setting that is different fromthe first setting. When stating that a stimulation pattern has asetting, it is understood that this means a stimulation pattern mayinclude at least one stimulation pulse having that setting. It is alsounderstood that, in some embodiments a stimulation pattern may includeone or more cardiac cycles where no stimulation pulse is delivered, inwhich case the pulse(s) may be viewed as being delivered at zero power.A stimulation pattern may include a plurality of identical pulses or asequence of pulses including two or more different settings. Twostimulation sequences in a pattern may differ in the order of pulsesprovided within a setting. Two or more stimulation sequences mayoptionally differ in their lengths (in time and/or number ofheartbeats). In some embodiments, a stimulation pattern may includepulses having BPR settings. In some embodiments, a stimulation patternmay include pulses that do not have BPR settings.

Examples of stimulation settings that are configured to reduce orprevent atrial kick in at least one ventricle may include any of thestimulation settings disclosed herein that are configured to cause areduction of a patients ventricular filling volume from the pretreatmentventricular filling volume. This may be caused by having at least partof an atrial contraction take place against a closed AV valve. Some suchexamples include:

-   -   a. Delivering one or more stimulation pulses to a ventricle of a        patient 0-50 ms before the onset of excitation in an atrium of        the patient. Optionally, this delay is set based on sensing of        atrial excitation. Optionally, this includes delivering one or        more stimulation pulses to the atrium 0-50 ms after the delivery        of stimulation pulses to the ventricle. Optionally, this is        performed at a rate that is slightly higher than the natural        heart rate of the patient.    -   b. Delivering one or more stimulation pulses to a ventricle of a        patient 0-70 ms after the onset of excitation in an atrium of        the patient. Optionally, this delay is set based on sensing of        atrial excitation. Optionally, this includes delivering one or        more stimulation pulses to the atrium 0-70 ms before the        delivery of stimulation pulses to the ventricle. Optionally,        this is performed at a rate that is slightly higher than the        natural heart rate of the patient.

Some embodiments may provide a system for reducing blood pressureconfigured to deliver stimulation at a rate higher than the naturalheart rate based on sensed natural heart rate or natural excitation. Forexample, the system may be configured to sense the natural excitationbetween delivery of stimulation pulses and if a natural activity issensed, the system may be configured to inhibit the delivery of thestimulation pulse to the chamber. If in a given time frame the amount ofsensed activations exceeds a threshold, the natural heart rate may beregarded as higher than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be increased, e.g., toaccommodate increased heart rate of a patient. On the other hand, if ina given time frame the amount of sensed activations is lower than athreshold (this threshold may be 0), the natural heart beat may beregarded as lower than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be reduced, e.g., to avoid overexcitation of a patient's heart. To achieve this effect, according toone embodiment, a system for reducing blood pressure may include asensor for sensing an excitation rate of at least one of an atrium and aventricle of a patient's heart, a stimulation circuit configured todeliver stimulation pulses to an atrium and a ventricle, and a processorcircuit coupled to the stimulation circuit. Optionally, a sensor forsensing the excitation rate of at least one of an atrium and a ventriclemay comprise an electrode for sensing atrial excitation. The processorcircuit may be configured to detect the patient's heart rate based onthe sensing and operate in an operating mode in which a stimulationpulse is provided to each of the at least one of an atrium and aventricle. The stimulation pulse may be delivered at a rate that ishigher than the sensed excitation rate and may be configured tostimulate the ventricle at a time between about 50 ms before and about70 ms after stimulation of the atrium.

Reducing atrial kick may have an immediate effect on blood pressurewhile hormone mediated mechanisms may take a longer period. While somedevices may be configured to have both an immediate and a hormonemediated effect, optionally, some of the BPR settings and/or stimulationpatterns may be configured to reduce or prevent atrial kick without asignificant increase in atrial stretch. For example, when the AV valvecloses at a time that atrial contraction is at peak pressure orthereafter, premature closure of the valve does not increase atrialstretch. Thus, in some embodiments, a device may be configured to causethe relative timing of atrial excitation and ventricular excitation tobe comparable with an AV delay that is at least 40 ms long or at least50 ms long. Atrial stretch may be measured, calculated, and/or estimatedas known in the art. In some embodiments, atrial stretch determinationmay include measuring atrial pressure. In some embodiments, atrialstretch determination may include measuring or estimating the dimensionof an atrium (e.g., diameter, size, or circumference).

In some embodiments, atrial kick may be reduced because the BPRstimulation setting may be set such that atrial contraction of a cardiaccycle is incomplete when the AV valve is open. In some embodiments,atrial contraction may take place completely or in part against a closedAV valve. In some embodiments atrial contraction may be prevented orreduced in force.

In some embodiments, only one or more ventricles may be stimulated andthe stimulation pulse may be timed to have an abnormal AV delay (e.g.,50 ms before to 120 ms after atrial excitation). In some embodiments, aBPR stimulation setting may include the delivery of at least oneelectrical pulse or stimulus to one or more atria. In some embodiments,this at least one atrial stimulus may cause atrial contraction. In someembodiments, the at least one atrial stimulus may interfere with atrialcontraction. In some embodiments, the at least one atrial pulse maycause an atrial spasm or another type of inefficient atrial contraction,

The reduction in blood pressure resulting from BPR stimulation may beobserved practically immediately upon application of the stimulationsignal (e.g., within 1 or 3 seconds (sec) or within 1, 3, or 5heartbeats) and may reach a minimal blood pressure value within lessthan 5 heartbeats from the beginning of stimulation,

By controlling the settings of BPR stimulation, one may control thedegree to which BP is reduced. This degree is sometimes patient specificand/or related to the precise positioning of one or more stimulationand/or sensing electrodes in or on the heart.

Adaptation

-   -   a. The inventors found that while stimulation is maintained,        blood pressure may display an adaptation pattern wherein blood        pressure increases after a time (some of which often occurs in a        short time being less than 5 minutes or even less than a        minute), and potentially reaches near pre-stimulation blood        pressure values (possibly due at least to baroreflex) or even        higher. The adaptation, at least in part, may be attributed to        changes in properties of the cardiovascular system, such as        increase in total peripheral resistance. The inventors further        found that termination of stimulation results in a quick return        of blood pressure to pre-stimulation values or even higher        values, and thereafter that the heart becomes responsive to the        blood pressure reducing stimulation signal at a degree similar        to a heart that was not so stimulated. In addition, it was found        that different stimulation patterns that comprise a plurality of        BPR stimulation settings result in different blood pressure        adaptation patterns.    -   b. Stimulation patterns may, for example, comprise at least a        first stimulation setting and a second stimulation setting        different from the first stimulation setting, the first        stimulation setting and the second setting configured to reduce        or prevent atrial kick. The stimulation pattern may even        comprise more than two different stimulation settings. The        second setting in some embodiments has a longer AV-delay than        the first setting. The second setting in some embodiments may        not be configured to reduce atrial kick.

In FIG. 1, the systolic blood pressure of a hypertensive patientreceiving a stimulation signal is plotted against time. The crossesalong the plotted line depict the peak systolic blood pressure for everyheartbeat. During approximately the first 2 plotted minutes, nostimulation signal was delivered. As seen, the patient's initial bloodpressure was on average more than 150 mmHg. The oscillations in bloodpressure (about ±10 mmHg) are attributed to the breathing cycle, asknown in the art.

Then, a first stimulation pattern was applied during time interval a-a′,a second stimulation pattern was applied during time interval b-b′, anda third stimulation pattern was applied during time interval c-c′. Inbetween the stimulation patterns and after the third stimulationpattern, the heart was not stimulated.

Attention is now drawn to FIG. 2, depicting an enlarged portion of FIG.1 marked by dashed rectangle A. During the time marked by the dashedrectangle in FIG. 2, which corresponds with the time interval a-a′ inFIG. 1, a stimulation commenced and was delivered to the patient's rightatrium and right ventricle, such that the atrium received a BPRstimulation signal (pulse) 2 ms before the ventricle. Stimulation endedat the time marked a′ in FIGS. 1 and 2. During the time interval a-a′,the patient's systolic pressure initially reduced to a minimal valuebelow 110 mmHg, and then gradually increased to intermediate values,between the initial blood pressure and the achieved minimum. At pointa′, stimulation stopped and an immediate overshoot in blood pressure wasobserved, to a value above 170 mmHg. Within about a dozen heartbeats,the blood pressure returned to its initial range.

The changes in blood pressure presented in FIGS. 1 and 2 represent, atleast in part, the cardiovascular system's response to changes in bloodpressure, known as the baroreflex. The baroreflex acts to restore bloodpressure to its pre-stimulation level by changing cardiovascularcharacteristics (e.g., peripheral resistance and/or cardiaccontractility). It may be assumed that the reduction in blood pressurethat resulted from the reduction in ventricular filling provoked abaroreflex response directed towards restoration of the pre-stimulationblood pressure. The effect of the baroreflex on the cardiovascularsystem is evident, for example, at point a′ in FIG. 2. At that point,the stimulation that affected ventricular filling was withdrawn andblood pressure immediately exceeded pre-stimulation blood pressure. Thismay be taken to indicate baroreflex changes to the cardiovascular system(e.g., peripheral resistance increased and contractility increased). Atpoint a′, where stimulation stopped and blood pressure peaked, thebaroreflex responded to the increase in blood pressure by again changingone or more characteristics of the cardiovascular system, this time inorder to lower the blood pressure to the level before the change. As canbe clearly seen, the response of the baroreflex feedback to increase anddecrease in blood pressure is asymmetric in that the response to anincrease in blood pressure is much faster than the response to adecrease in blood pressure. Some embodiments may make use of thisasymmetry of the baroreflex to reduce or even prevent adaptation of thereduction in blood pressure due to reduced filling, for example, bycontrolling a stimulation pattern accordingly, as detailed herein.

FIG. 3A depicts an enlarged view of the curve of FIG. 1 between timepoint a and point a′. In FIG. 3A, an exponential function was fitted tothe plotted curve showing an adaptation response, the functiondescribing a relation between time and SysBP, and having the followingformula:P=Pi+DP(1−e ^(−t/k))

Where P (in mmHg) denotes the systolic blood pressure, Pi (mmHg) is afirst average reduced blood pressure upon commencement of BPRstimulation, DP (mmHg) is a constant representing the amount of increasein pressure after the initial decline to a new steady state level, k(sec) is a response time constant, e is the mathematical constant, beingthe base of the natural logarithm, and t (sec) is time.

In FIG. 3A, the matching function was as follows:P=115+23(1−e ^(−t/15.5))

Where Pi was found to be 115 mmHg, DP was 23 mmHg, and k was 15.5 sec.

FIG. 3B depicts an enlarged view of the portion of FIG. 1 marked bydashed rectangle A′. In FIG. 3B, an exponential function was fitted tothe plotted curve showing an adaptation response to the termination ofthe delivery of BPR stimulation. As seen, this response, whichmanifested in a reduction of blood pressure, was faster than theresponse to BPR stimulation.

In FIG. 3B, the matching function was as follows:P=190−35(1−e ^(−t/4.946))

Where Pi was found to be 190 mmHg, DP was −35 mmHg, and k was 4.946 sec.

As mentioned above, the baroreflex response to a reduction in bloodpressure is much slower than the baroreflex response to an increase inblood pressure. This is indicated by the ratio of the aforementionedtime constants k (about 15 sec to about 5 sec) with a much fasterresponse to the increase in blood pressure. This asymmetry in the speedof the baroreflex response may provide means to design a stimulationpattern that generates an average reduction in blood pressure andreduction or even prevention of adaptation. For example, in a preferredembodiment, a stimulation pattern may alternate between two stimulationsettings in a way that the weighted response favors the changes in thecardiovascular system invoked by increase in blood pressure. In thisembodiment, the heart may be stimulated using a stimulation patternhaving two stimulation settings: the first setting designed to reduceventricular filling and thereby reduce blood pressure, and the secondsetting designed to have normal ventricular filling, or at least ahigher ventricular filling, than that of the first setting. Thisstimulation pattern may comprise pulses having the first setting (BPR)delivered for a period of time that is shorter than the time constant ofthe baroreflex response to the decrease in blood pressure. In such case,adaptation may begin to manifest and blood pressure may increase fromthe reduced level, but may not reach its pre-stimulation level. Thestimulation pattern may also comprise pulses having the second setting(e.g., natural AV delay) delivered for a period of time that is longerthan the time constant of the baroreflex response to increase in bloodpressure. In this case, full advantage may be taken of the baroreflexcaused reduction in blood pressure, and blood pressure may even returnto its level before the stimulation pattern switched to this secondsetting. The weighted response of the baroreflex in such a pattern mayreduce or prevent adaptation while the average pressure may be lowerthan a pre-stimulation level. The relation between the time constantsand the period of time allotted to the delivery of pulses havingdifferent settings may determine the level of baroreflex response thattakes effect during the whole stimulation pattern. If, for a givenstimulation setting, the period of delivery is selected to be shorterthan the time constant of response, the baroreflex may not be able tochange the cardiovascular system back to a pre-stimulation level, and ifthe period selected is greater than the time constant, the baroreflexeffect may be more pronounced.

As seen in FIG. 1, at the interval between points b and b′, a secondstimulation pattern was delivered. FIG. 4 depicts an enlarged version ofthis portion of FIG. 1 (marked by dashed rectangle B in FIG. 1). In thesecond stimulation pattern, a sequence of 12 BPR pulses were deliveredto both an atrium and a corresponding ventricle at an AV delay of 2 ms,followed by 3 heartbeats at which only atrial stimulation and noventricular stimulation was artificially delivered. During these last 3heartbeats, ventricular excitation occurred by the natural conductancethrough the AV node that resulted in an AV delay of ˜180 ms. This secondstimulation pattern was repeated for the duration of the shown timeinterval. In FIG. 4, the exponential function matching the curve wasfound to be the following:P=112+30(1−e ^(−t/25.5))

As seen, Pi and also DP were comparable to the corresponding values ofthe first stimulation pattern (a-a′ in FIG. 3A). However, k of thesecond pattern was nearly twice the time constant of the firststimulation pattern. In this time interval, adaptation occurred at aslower rate than in FIG. 3A, but blood pressure spiked more than it didin FIG. 3A when the pattern switched between the stimulation pulses.This result demonstrates that the use of a stimulation pattern havingalternating stimulation settings reduced adaptation.

A third stimulation pattern was delivered as well, as seen in FIG. 1,between points c and c′. FIG. 5A depicts an enlarged view of the portionof FIG. 1 marked by dashed rectangle C, which includes the portion ofthe curve between point c and point c′. In the third stimulationpattern, a sequence of 12 BPR pulses was delivered at an AV delay of 2ms, followed by 3 BPR pulses, each with a 120 ms AV delay. This wasrepeated for the duration of the shown time interval.

The portion of the curve of FIG. 5A that is marked by a dashed rectangleis plotted in FIG. 5B. In FIG. 5B, an exponential function was fitted tothe plotted curve showing an adaptation response to the delivery of thestimulation pattern of 12 BPR pulses delivered at an AV delay of 2 msfollowed by 3 BPR pulses, each with a 120 ms AV delay.

In FIG. 5B, the matching function was as follows:P=109.7+22.3(1−e ^(−t/45.4))

Where Pi was found to be 109.7 mmHg, DP was 22.3 mmHg, and k was 45.4sec. As seen, while the initial reduction in blood pressure wascomparable with the one shown in FIG. 3A (Pi=115 or 109.5), theadaptation time constant (k) was much higher (45.4 sec v. 15.5 sec),meaning that a low blood pressure was maintained for a period of timethat is about 3 times greater than in FIG. 3A.

Attention is now drawn to FIG. 6, wherein a hypertensive patient's heartwas stimulated at a stimulation pattern having a sequence of 12 BPRpulses delivered at an AV delay of 2 ms, followed by 3 BPR pulses, eachwith an 80 ms AV delay.

As seen, in this case, the adaptation rate was very low and almostundetectable at the allotted time interval. An exponential formula couldnot be matched, suggesting that the adaption was extremely slow or didnot exist.

In FIG. 7, a hypertensive patient's heart was stimulated with astimulation pattern having a sequence of 12 BPR pulses delivered at anAV delay of 2 ms, followed by 3 BPR pulses, each with a 40 ms AV delay.Stimulation commenced at point t₁ and ended at point t₂. There was nomeasured adaptation response and the fitting curve was in fact linearand had a fixed average reduced blood pressure of about 112 mmHg, whichis about 31 mmHg lower than the blood pressure immediately before andafter the time interval t₁-t₂.

As apparent from the different stimulation patterns shown before, astimulation pattern comprising at least one BPR stimulation can be setto at least approach one or more targets. For example, in someembodiments, a stimulation pattern may be set to cause an initialreduction in blood pressure (systolic and/or diastolic) that will exceeda predetermined threshold or will be within a predetermined range. In amore specific embodiment, the blood pressure may be reduced by at leasta given percentage or by at least a given measure (e.g., 10 or 20 mmHgor even 30 mmHg) or the blood pressure may be reduced to be within agiven range (e.g., between 90 and 130 mmHg SysBP) or below a giventarget (e.g., 130 mmHg SysBP or less). In some embodiments, a target mayinclude maintaining a reduced blood pressure for a prolonged period oftime within a reduced average range. For example, the pretreatment bloodpressure may be reduced to a predetermined average blood pressure for aperiod of time or a number of heartbeats. In another embodiment, thetarget may include causing a given percentage of heartbeats to be at thereduced range/threshold. In some embodiments, the target may includereducing blood pressure while also reducing the level of spikes betweenstimulation pulses. For example, a stimulation pattern may be used tolower the blood pressure to a constant blood pressure for apredetermined interval of time. In some embodiments, a stimulationpattern may be used to lower the blood pressure without significantlyinfluencing the cardiac output. For example, applying intermittent BPRpulses may allow pulses with a higher (or even full) atrial kick tooccur between BPR pulses. The pulses with a higher (or even full) atrialkick may prevent the BPR pulses from significantly lowering the cardiacoutput. In another embodiment, reducing adaptation that relates tolowering total peripheral resistance together with reduction of bloodpressure (afterload) can positively affect cardiac output by affectingflow via the blood system. In yet another embodiment, pacing at a higherrate than the patient's natural rhythm may avoid a negative effect oncardiac output that might be associated with lower stroke volume.

In some embodiments, a time constant of the change in blood pressure ofa given pattern may be calculated and the stimulation pattern may be setto have one or more BPR stimulation parameters for an amount of time ornumber of heartbeats that are set as a certain percentage of thecalculated time constant. For example, in FIGS. 3A and 3B, k wasmeasured to be about 15 sec for the rate of increase in blood pressureduring delivery of a BPR pulses and about 4.9 sec for the rate ofadaptation to the termination of the delivery of BPR pulses. In someembodiments, it may be desired to prevent blood pressure from increasingbeyond a given value, in which case, the period of delivery of the BPRpulses may be selected to be significantly smaller than k (e.g., 30% to60% of k). In this embodiment, the interval may be selected to be lessthan 15 sec. Such an interval may include about 6-10 sec or about 8-14heartbeats where the heart rate is about 80 heartbeats per minute.

Optionally, it is desired to take advantage of the adaptation responseto the withdrawal of BPR pulses. In such case, a greater portion of kmight be applied. For example, based on FIG. 3B, a period of 3-5heartbeats may be selected (where k is about 4.9 sec). Thus, forexample, based on FIGS. 3A and 3B, the inventors applied the stimulationpattern of FIG. 4.

The stimulation pattern may be set, for example, to be the best of aplurality of stimulation patterns (i.e., the one closest to a set targetparameter) and/or it may be selected as the first tested stimulationpattern that conformed to a set target.

Embodiments of Methods for Setting and/or Selecting a StimulationPattern

An exemplary method 600 for setting and/or selecting a stimulationpattern is schematically depicted in FIG. 8. Method 600 may be performedduring implantation of a device for performing BPR stimulation and/orperiodically to adjust the device operation parameters and/orcontinuously during operation. Method 600 may be performed by system700, described below. Accordingly, system 700 may be configured toperform any step of method 600. Similarly, method 600 may include anysteps system 700 is configured to perform. For example, method 600 mayinclude any of the functions discussed below with respect to system 700.Additionally, method 600 may be performed by device 50, described below.Method 600 may include any steps device 50 is configured to perform.

Throughout the present disclosure, the terms “first,” “second,” and“third” are not meant to always imply an order of events. In some cases,these terms are used to distinguish individual events from one anotherwithout regard for order.

In some embodiments, step 601 may include setting a target bloodpressure value. This target may be an absolute blood pressure value(e.g., a target blood pressure range, a target threshold of spike value,and/or number or portion of spikes in a given timeframe), a relativevalue (e.g., as compared with the pretreatment blood pressure of thepatient or as a comparison between a plurality of tested stimulationpatterns), or both. The target blood pressure value may be a bloodpressure value (e.g., measured in mmHg) and/or a value associated with aformula calculated to match a blood pressure measurement of astimulation pattern, etc. This target blood pressure value may be setbefore, during, and/or after the other method steps and it may also beamended, for example, if not reached by any tested simulation pattern.

Step 602 may include delivery of one or more stimulation patterns,including a first stimulation pattern, to one or more chambers of apatients heart. The first stimulation pattern may be a genericstimulation pattern or the first stimulation pattern may already beselected to match a given patient (e.g., when implanting a replacementdevice). The first stimulation pattern may include at least onestimulation setting configured to reduce or prevent atrial kick in atleast one ventricle for a first time interval.

Step 603 may include sensing one or more parameters before, during,and/or after the delivery of each of one or more stimulation patterns(step 602). The sensed parameter(s) may comprise a blood pressure valueor a blood pressure related parameter (e.g., a change in bloodpressure). In some embodiments, the sensed parameter(s) may compriseinformation relating to the timing and/or extent of closure and/oropening of an AV valve. In some embodiments, the sensed parameter(s) maycomprise information relating to the timing and/or rate of blood flowbetween an atrium and ventricle of the heart. In some embodiments, thesensed parameter(s) may include sensing pressure within a heart chamber(e.g., an atria and/or ventricle). In some embodiments, sensing of apatient's AV valve status, or position, (i.e., opened or closed) mayinclude sensing of heart sounds, for example, using audio sensors. Insome embodiments, sensing of a patient's AV valve status may includeDoppler sensing and/or imaging of cardiac movement. In some embodiments,the patient's AV valve status may be sensed by a blood flow sensor.

In some embodiments, sensing of blood flow may be performed by one ormore implanted sensors in one or more cardiac chambers. For example, oneor more pressure sensors may be placed in the right ventricle. In someembodiments, a plurality of pressure sensors may be placed in aplurality of chambers. Optionally, measurements of a plurality ofsensors may be combined. Optionally, pressure changes, trends ofpressure changes, and/or pressure change patterns may be used to provideinformation relating to blood flow. In some embodiments, comparingrelative changes between two or more sensors in different chambers maybe used.

When a stimulation pattern is delivered to a heart (step 602), the oneor more parameters may be measured at least once during delivery of thestimulation pattern or at a plurality of times or even continuously.Each stimulation pattern may be delivered more than once.

Step 604 may include analyzing the sensed parameter(s). In someembodiments, once at least one stimulation pattern is delivered andcorresponding parameter(s) are sensed, analysis may be performed (604).In embodiments in which multiple parameters are sensed, step 604 mayinclude the following: comparing sensed parameter values to a target;comparing sensed parameters between two or more stimulation patterns;comparing calculated values (e.g., the k constant) relating to two ormore stimulation patterns; and comparing additional sensed parametersbetween two or more stimulation patterns. In some embodiments, this lastfunction may be performed to determine and select which stimulationpattern yields a higher ejection fraction, stroke volume, cardiacoutput, and/or a lower battery use.

Step 605 may include setting a pacing (stimulation) pattern. When morethan one parameter is sensed, the stimulation pattern used in step 605may be selected based on the plurality of parameters, a plurality oftarget values, and/or a plurality of target ranges.

In some embodiments, the steps shown in FIG. 8 may be performed in theorder shown by the arrows in FIG. 8. In other embodiments, the steps maybe performed in another order. For example, step 602 may be performedbefore setting a target blood pressure value in accordance with step601. In some embodiments, a stimulation pattern may be set to beperformed indefinitely. In some embodiments, a stimulation pattern maybe set to be performed for a predetermined period of time. For example,in some embodiments, the stimulation pattern set during step 605 may beperformed for a predetermined period of time and then step 602, step603, and step 604 may be repeated to determine how another stimulationpattern affects the patient's blood pressure. Then, based on theanalysis performed in step 604, step 605 may also be repeated.

In some embodiments, method 600 may include a step of adjusting a firststimulation pattern, thus making the first stimulation pattern into asecond stimulation pattern. In some embodiments, step 605 of setting astimulation pattern may include adjusting a stimulation pattern. Forexample, step 605 may include adjusting a parameter of a firststimulation setting, e.g., the time interval from step 602. In anotherembodiment, step 605 may include adjusting a parameter of a firststimulation setting configured to reduce or prevent the atrial kick inat least one ventricle. In some embodiments, step 605 may includeadjusting first stimulation pattern to be a second stimulation patternconfigured to cause a reduction in blood pressure by at least apredetermined amount. In some embodiments, the predetermined amount mayinclude, for example, about 8 mmHg to about 30 mmHg. In someembodiments, the predetermined amount may be at least 4% of a patient'spretreatment blood pressure. For example, the predetermined amount maybe about 4% of a patient's pretreatment blood pressure to about 30% of apatient's pretreatment blood pressure.

In some embodiments, step 605 may include adjusting the stimulationpattern to be a stimulation pattern configured to cause an immediatereduction in blood pressure by at least a predetermined amount. Forexample, in some embodiments, step 605 may include adjusting thestimulation pattern to be a stimulation pattern configured to cause areduction in blood pressure by at least a predetermined amount withinabout 3 sec from an application of electricity to the heart. In someembodiments, step 605 may include adjusting the stimulation pattern tobe a stimulation pattern configured to cause a reduction in bloodpressure by at least a predetermined amount within at least 5 heartbeatsof the applied electricity. In some embodiments, the reduction in bloodpressure resulting from a stimulation pattern set during step 605 mayoccur within 1-3 sec of the application of electricity to the heart orwithin 1, 3, or 5 heartbeats of the application of electricity to theheart.

In some embodiments, the reduction in blood pressure resulting from astimulation pattern set during step 605 may be such that a patient'saverage blood pressure at rest is at least 8 mmHg below the patient'sinitial blood pressure at rest. In some embodiments, the reduction inblood pressure resulting from a stimulation pattern set during step 605may be maintained for at least 1 minute. In some embodiments, thereduction in blood pressure resulting from a stimulation pattern setduring step 605 may be maintained for at least 5 minutes. In someembodiments, the blood pressure may reach a minimal blood pressure valuewithin less than 5 heartbeats from the beginning of stimulation. Forexample, step 605 may include adjusting a first stimulation pattern tobe a second stimulation pattern configured to cause a reduction in bloodpressure. In some embodiments, step 605 may include adjusting the firststimulation pattern to a second stimulation pattern configured to causea reduction in blood pressure for a predetermined time interval. Forexample, the predetermined time interval may include at least 1 minuteor at least 5 minutes.

In some embodiments, the second stimulation pattern may be configured tomaintain a blood pressure that does not exceed a predetermined averagevalue during the predetermined interval by more than a predetermineddegree. For example, the predetermined degree may be a difference ofabout 20 mmHg or less. In some embodiments, the predetermined degree maybe a difference of about 1 mmHg to about 8 mmHg.

In some embodiments, the second stimulation pattern may include a secondstimulation setting configured to reduce or prevent the atrial kick inat least one ventricle. The second stimulation setting may be based uponat least one blood pressure variation parameter calculated from an inputdata sensed during application of the first stimulation pattern.

In some embodiments, the second stimulation pattern may be configured toreduce or limit the magnitude of spikes in blood pressure betweenstimulation pulses. In some embodiments, the spikes in blood pressurebetween stimulation pulses may be reduced to a percentage of a baselineblood pressure value. For example, the second stimulation pattern may beconfigured to prevent more than an 80% increase in blood pressurebetween pulses. In other words, the second stimulation pattern may beconfigured to prevent the blood pressure from spiking more than about80% between pulses. In some embodiments, the second stimulation patternmay be configured to prevent more than a 40% increase in blood pressurebetween pulses. In some embodiments, the second stimulation pattern maybe configured to prevent a blood pressure spike of more than about 10mmHg to about 30 mmHg between pulses. For example, in some embodiments,the second stimulation pattern may be configured to prevent a bloodpressure spike of more than 20 mmHg between pulses.

In some embodiments, the second stimulation pattern may comprisemultiple stimulation pulses. At least one stimulation pulse of themultiple stimulation pulses may have a first stimulation settingconfigured to reduce atrial kick in at least one ventricle. At least onestimulation pulse of the multiple stimulation pulses may have a secondstimulation setting configured to reduce the baroreflex response to thereduction in atrial kick such that the increase in blood pressure valuesoccurring between stimulation pulses is limited to a predeterminedvalue. In some embodiments, the second stimulation setting may beconfigured to increase blood pressure for about 1 heartbeat to 5heartbeats to invoke negation of the baroreflex response. In someembodiments, the second stimulation pattern may include multiplestimulation pulses having the first stimulation setting and multiplestimulation pulses having the second stimulation setting. In suchembodiments, between about 1% of the multiple stimulation pulses and 40%of the multiple stimulation pulses of the stimulation pattern may havethe second stimulation setting. In some embodiments, the secondstimulation pattern may include multiple stimulation pulses having thefirst stimulation setting and multiple stimulation pulses having thesecond stimulation setting. In such embodiments, between about 1% of themultiple stimulation pulses and 40% of the multiple stimulation pulsesof the stimulation pattern may have the second stimulation setting. Insome embodiments, the stimulation pattern may include a ratio ofstimulation pulses having the first setting to the stimulation pulseshaving the second setting based on a ratio of time constants of theresponse to increase and decrease in blood pressure. For example, theratio of stimulation pulses having the first setting to the stimulationpulses having the second setting may be based on a ratio of the timeconstants of the changes in blood pressure resulting from each of thefirst setting and the second setting. In some embodiments, the firststimulation setting may include a first AV delay and the secondstimulation setting may include a second AV delay, the first AV delaybeing shorter than the second AV delay. In some embodiments, the secondstimulation pattern may include multiple stimulation pulses having thefirst stimulation setting and one or more stimulation pulses having thesecond stimulation setting. In some embodiments, the second stimulationpattern may include a ratio of about 8 stimulation pulses to about 13stimulation pulses having the first setting to about 2 stimulationpulses to about 5 stimulation pulses having the second setting. In someembodiments, the second stimulation pattern may include at least onestimulation pulse having a stimulation setting configured to invoke ahormonal response from the patient's body. In some embodiments, thefirst stimulation pattern may include at least one stimulation pulsehaving a stimulation setting configured not to invoke a hormonalresponse from the patient's body. In some embodiments, the secondstimulation pattern may be applied before the first stimulation patternin a given sequence of stimulation patterns.

In some embodiments, method 600 may include alternating between two ormore stimulation patterns. For example, method 600 may includealternating between two to ten stimulation patterns.

In some embodiments, the blood pressure sensor and the controller may beconfigured to operate at least partially as a closed loop.

In some embodiments, method 600 may include the controller executing aplurality of stimulation patterns and receiving for each of thestimulation patterns a corresponding input data relating to a patient'sblood pressure during the stimulation. The plurality of stimulationpatterns may include at least two stimulation patterns each comprisingat least one stimulation pulse having a stimulation setting configuredto reduce or prevent the atrial kick in at least one ventricle. The atleast two stimulation patterns may differ from one another by the numberof times or the length of time the at least one stimulation pulse isprovided in sequence. The at least two stimulation patterns may differfrom one another by the number of times or the length of time apredetermined AV delay occurs in sequence. In some embodiments, thestimulation setting may be identical in each of the at least twostimulation patterns. In some embodiments, the stimulation setting mayinclude an identical AV delay for each of the at least two stimulationpatterns. In some embodiments, the at least two stimulation patterns maydiffer from one another by one or more stimulation settings includedwithin each of the at least two stimulation patterns.

In some embodiments, method 600 may include the controller calculatingfor each of the plurality of stimulation patterns at least one bloodpressure variation parameter relating to the input data. Method 600 mayinclude the controller adjusting the stimulation pattern according tothe blood pressure variation parameter. In some embodiments, method 600may include the controller adjusting the stimulation pattern to be thestimulation pattern with the best blood pressure variation parameter.For example, the best blood pressure variation parameter may include theblood pressure variation parameter that displays the lowest degree ofbaroreflex. The best blood pressure variation parameter may include theblood pressure variation parameter that displays a baroreflex within apredetermined range.

In some embodiments, the second stimulation pattern may include at leastone stimulation pulse having a stimulation setting configured to invokea hormonal response from the patient's body, while in some embodiments,the first stimulation pattern may include at least one stimulation pulsehaving a stimulation setting configured not to invoke a hormonalresponse from the patient's body.

In some embodiments, the plurality of stimulation patterns may include afirst stimulation pattern and a second stimulation pattern executedafter the first stimulation pattern. The second stimulation pattern mayhave at least one stimulation setting that was set based on an algorithmusing blood pressure variation parameters relating to the input data ofthe first stimulation pattern.

Embodiments of Systems for Reducing Blood Pressure

FIG. 9 schematically depicts an exemplary system 700 for reducing bloodpressure according to some embodiments. System 700 may be a device ormay comprise a plurality of devices, optionally associated by wire orwireless communication. The device(s) may have multiple componentsdisposed inside a housing and/or connected to the housing electronicallyand/or by wires. As shown in FIG. 9, a heart 701 is connected to asystem 700 by one or more stimulation electrodes 702. The stimulationelectrode(s) may be configured to stimulate at least one chamber of aheart of a patient with a stimulation pulse. In some embodiments,multiple electrode(s) 702 may each be positioned in a different chamberof the heart. For example, one electrode may be positioned in an atriumand another electrode may be positioned in a ventricle. In someembodiments, multiple electrodes 702 may be positioned in a singlechamber. For example, two electrodes may be positioned in an atriumand/or two electrodes may be positioned in a ventricle. In someembodiments, one electrode may be positioned in first chamber andmultiple electrodes may be positioned in a second chamber.

In the present embodiment, the electrode(s) 702 may include typicalcardiac pacemaker leads, such as the Medtronic Capsure® pacing leads.These leads are used to connect the heart 701 to system 700. The pacingleads may be constructed with an industry standard IS-1 BI connector atone end (reference standard ISO 5148-3:2013), electrodes at the otherend, and an insulated conductor system between them. In someembodiments, the IS-1 BI connector is constructed using stainless steelfor the two electrode contacts and silicone as an insulating material.Some embodiments may use polyurethane as an insulating material.

Stimulation of one or more cardiac chambers may be accomplished byplacing a voltage between the two electrodes of the atrial orventricular cardiac pacing leads described above. The stimulationcircuit uses a network of transistors (e.g., MOSFETS) to charge acapacitor to a specific programmable voltage, such as 2.0V, and thencontrol its connection to the electrodes for a fixed period ofprogrammable time, such as 0.5 ms. The same network may also manage adischarge of any residual charge that may be accumulated on theelectrodes after stimulation is complete. The same network may controlthe type of stimulation applied, such as bipolar (between the twoelectrodes) or unipolar (between one electrode and the stimulatorhousing).

One or more electrodes may be placed in contact with one or bothventricles and/or one or both atria, as known in the art. Suchelectrodes may be used to sense and/or deliver stimuli to the respectivecardiac chamber(s). For example, pacing electrodes can be introduced toboth ventricles, with one electrode implanted into the right ventricleand an additional electrode placed on the left ventricle through thecoronary sinus, and with the system 700 including means to generatebiventricular stimulation of both ventricles in order to reducedyssynchrony caused by ventricular stimulation.

System 700 may include a controller 703. System 700 may be an electricalstimulator including a power source 704 (e.g., a battery as known in theart of electrical stimulators). Controller 703 and/or electrode(s) 702may draw power from power source 704.

Optionally, the electrical stimulator of system 700 is constructed of ahermetically sealed housing and a header. The housing may be constructedof titanium or any other biocompatible material, and may contain a powersource 704, electronics, and a telemetry coil or communication module707 for communication with an external device. The power source 704 maybe an implantable grade, hermetically sealed, primary battery. Thebattery chemistry may be lithium-iodine. Other embodiments may uselarger or smaller batteries. Other embodiments may use rechargeablebatteries such as Li-ion rechargeable batteries. The electronics in someembodiments may be constructed of standard off-the-shelf electronics(e.g., transistors and diodes) and/or custom electronics (e.g., ASIC).

In order to detect the onset of atrial excitation and/or ventricularexcitation, one or more sensing electrodes may be implanted at or near asite of interest in the heart. These sensing electrodes may be the sameelectrodes used for delivering pulses to the heart or dedicated sensingelectrodes. The electrical activity may be band-pass filtered to removeunwanted noise and may conform to an international standard for cardiacpacemakers (reference EN45502-2-1:2003), with programmable cutofffrequencies. An electrical circuit may be used to amplify the electricalsignals generated by a propagating activation of the cardiac chamber andto determine the onset of activation once the electrical signals fulfillspecified criteria, for example, crossing of a predefined threshold. Thesignal may, for example, be amplified, with programmable gains, and thenpassed to a comparator for threshold detection, with programmabledetection thresholds in steps of 0.2 mV (atrial) and 0.4 mV (ventricle).These means of detecting excitation may introduce a delay between theactual onset of activation in the chamber and its detection, since thedetecting electrodes may be away from the origin of excitation and thetime it takes for the signal to fulfill the detection criteria might notbe negligible and may be in the range of 5 to 50 ms or even more. Insuch cases, the timing of the onset of excitation may be estimated basedon the timing of a sensed excitation, and the delivery of stimulationpulses would be calculated to compensate for this delay.

Optionally, the controller 703 interfaces with an accelerometer tomeasure patient activity level. This patient activity level may be usedto adjust the pacing rate and/or BPR settings and/or the stimulationpattern based upon the patient's needs. Activity level may also be usedto control a desired level of effect on blood pressure. For example,reduction in blood pressure may be reduced at high levels of activity toenable better performance when an increase in blood pressure isrequired. Optionally, when a patient is inactive (e.g., when sleeping)blood pressure may reduce naturally, in which case pacing may beadjusted in order to avoid reducing blood pressure below a desiredthreshold. Activity level may also be used to adjust settings based onbaroreflex to allow better response when needed. The sensor may be, forexample, a piezoelectric sensor. Other embodiments may use a MEMS-basedaccelerometer sensor. Other embodiments may use a minute ventilationsensor, optionally in combination with an accelerometer.

Controller 703 may be configured to deliver electricity to the heart 701via one or more electrodes 702. Controller 703 may be configured toexecute a stimulation pattern of stimulation pulses according to anyembodiment of this disclosure. In some embodiments, the stimulationpulses may be delivered to at least a ventricle of the heart. In someembodiments, the stimulation pattern may include a first stimulationsetting and a second stimulation setting different from the firststimulation setting, with the first stimulation setting and the secondsetting configured to reduce or prevent the atrial kick. In someembodiments, the first stimulation setting has a different AV delay thanthe second stimulation setting. In some embodiments, the firststimulation setting and/or the second stimulation setting may beconfigured such that maximum atrial stretch is at a value that is aboutequal to or lower than the maximum atrial stretch of the same heart whennot receiving stimulation. In some embodiments, the first stimulationsetting and/or second stimulation setting are configured to cause anatrium to be at maximum force when the AV valve is open. In someembodiments, the first stimulation setting and/or second stimulationsetting are configured to alter the mechanics of at least one atrialcontraction such that the mechanics of the at least one atrialcontraction are different from the mechanics of a previous naturalatrial contraction. In some embodiments, the first stimulation settingand/or second stimulation setting are configured to reduce the force ofat least one atrial contraction. In some embodiments, the firststimulation setting and/or second stimulation setting are configured toprevent at least one atrial contraction.

In some embodiments, the controller 703 may be configured to deliver avariety of different AV delays. The controller 703 may be configured tosense when the atrial contraction or excitation occurs (as describedherein) and then deliver ventricular stimulation a fixed interval afterthat or before a future anticipated atrial excitation or contraction.The interval may be programmable. The controller 703 may also beconfigured to stimulate the atrium and then deliver ventricularstimulation at a fixed interval after that, which may also beprogrammable. The programmable interval may, for example, be changedbetween 2 ms and 70 ms to accommodate a desired therapeutic effect oreven provide a negative AV delay of up to −50 ms.

In some embodiments, controller 703 may be configured to repeat astimulation pattern multiple times. For example, controller 703 mayrepeat a stimulation pattern twice. In another embodiment, controller703 may be configured to repeat a stimulation pattern at least twice ina period of an hour. The stimulation pattern repeated by controller 703may include any type of stimulation pattern. For example, thestimulation pattern may include a stimulation setting configured toreduce or prevent the atrial kick in at least one ventricle. In anotherembodiment, the stimulation pattern may include two differentstimulation settings each configured to reduce or prevent the atrialkick in at least one ventricle. These two stimulation settings maydiffer by one or more parameters, for example, by AV delay.

In some embodiments, controller 703 may be configured to execute one ormore consecutive stimulation patterns for a predetermined time interval.For example, in some embodiments, the time interval may be 10 minutes orlonger. In another embodiment, the time interval may be 30 minutes orlonger, one hour or longer, or 24 hours or longer. In some embodiments,the time interval may be a period of months, such as one month to oneyear. In some embodiments, the time interval may be longer than oneyear. In some embodiments, the one or more consecutive stimulationpatterns may include a first stimulation setting configured to reduce orprevent the atrial kick in at least one ventricle for a portion of thetime interval. For example, the one or more consecutive stimulationpatterns may include a first stimulation setting configured to reduce orprevent the atrial kick in at least one ventricle for about 50% of atime interval to about 100% of the time interval. In another embodiment,the one or more consecutive stimulation patterns may include a firststimulation setting configured to reduce or prevent the atrial kick inat least one ventricle for about 50% of a time interval to about 85% ofthe time interval. In some embodiments, the one or more consecutivestimulation patterns may include a second stimulation setting having alonger AV delay than the first stimulation setting for at least oneheartbeat during the time interval. In some embodiments, the one or moreconsecutive stimulation patterns may include a second stimulationsetting and/or a third stimulation setting. The second stimulationsetting and/or third stimulation setting may each be different from thefirst stimulation setting. In some embodiments, the second stimulationsetting and/or third stimulation setting may each be configured toreduce or prevent the atrial kick in at least one ventricle. In someembodiments, the second stimulation setting and/or third stimulationsetting may each be configured not to reduce or prevent the atrial kickin at least one ventricle. In some embodiments, the second stimulationsetting and/or third stimulation setting may include about 0% of a timeinterval to about 50% of the time interval. In some embodiments, thesecond stimulation setting and/or third stimulation setting may includeabout 0% of a time interval to about 30% of the time interval. In someembodiments, the second stimulation setting and/or third stimulationsetting may include about 0% of a time interval to about 20% of the timeinterval. In some embodiments, the second stimulation setting and/orthird stimulation setting may include about 5% of a time interval toabout 20% of the time interval.

In some embodiments, controller 703 may be configured to execute one ormore consecutive stimulation patterns including a sequence of 10-60stimulation pulses having a first stimulation setting configured toreduce or prevent the atrial kick in at least one ventricle. In someembodiments, controller 703 may be configured to execute one or moreconsecutive stimulation patterns including a sequence of 1-10 heartbeatsembedded within the 10-60 stimulation pulses and the sequence of 1-10heartbeats may have a longer AV delay than the first stimulationsetting. For example, the 10-60 stimulation pulses may include 5stimulation pulses having the first stimulation setting, followed by oneheartbeat having a longer AV delay than the first stimulation setting,followed by 50 stimulation pulses having the first stimulation setting.The sequence of 1-10 heartbeats may include at least one stimulationpulse having a first stimulation setting configured to reduce or preventthe atrial kick in at least one ventricle. The sequence of 1-10heartbeats may include a natural AV delay. The sequence of 1-10heartbeats may occur without stimulation.

System 700 may further comprise one or more sensors 705. In someembodiments, such sensor(s) 705 may include one or more sensingelectrode(s) for sensing electrical activity of the heart. In someembodiments, one or more sensing electrode(s) may include one or morestimulation electrode(s) 702. In some embodiments, sensor(s) 705 mayinclude one or more blood pressure sensors (implantable and/orexternal). In some embodiments, one or more sensors 705 may include oneor more pressure sensors implanted in the heart (e.g., in the atriaand/or ventricle). In some embodiments, sensor(s) 705 may include one ormore blood flow sensors (implantable and/or external). For example, oneor more sensors 705 may include ultrasound sensing of blood flow throughthe AV valve. In some embodiments, sensor(s) 705 may include one or moresensors configured to monitor the timing of closure of the AV valve. Oneor more of these sensors may be configured to operate as a closed loopwith the controller.

Information from sensor(s) 705 may be provided to controller 703 by anyform of communication, including wired communication and/or wirelesscommunication. Optionally, system 700 may comprise one or morecommunication modules 707 for receiving and/or transmitting informationbetween system components and/or to devices that are external to thesystem. In some embodiments, controller 703 may be configured to receiveinput data relating to the patient's blood pressure. For example, theinput data relating to the patient's blood pressure may include dataindicative of BP measured at one or more points in time or of avariation in BP (e.g. a degree of change and/or a rate of change or afunction describing the change of blood pressure over time) and/orstatistical data relating to BP or variation in BP, maximum and/orminimum BP values

Optionally, system 700 may comprise one or more user interfaces 708 forproviding information and/or for allowing input of information.Providing information may include, for example, a display of operationalinformation relating to the system and/or data that was recorded by thesystem and/or received by the system during operation. This may includesensed parameter(s) and/or a relation between sensed parameter(s) andoperational information (such as stimulation pattern settings and/orrelative timing between delivery of a given pace and sensedinformation).

Optionally, user interface 708 may be comprised of a commerciallyavailable laptop computer (e.g., Windows®-based computer) running asoftware application. The software application may serve to generateorders to be delivered to an interface that is, in turn, connected to ahand-held wand that contains a telemetry circuit for communication withthe implantable stimulator. The orders sent to the wand may be used toset stimulation parameters and/or to retrieve device diagnostics, devicedata, cardiac data, and real-time cardiac sensing. The interface alsoallows for connection of a 3-lead ECG and this data is displayed on thelaptop computer screen by the software application. Other embodimentsmay not include the 3-lead ECG circuitry or may include 12-lead ECGcircuitry. Other embodiments may incorporate the functionality of thewand, interface, and laptop computer into a dedicated piece of hardwarethat performs all three functions. Other embodiments may also addprinting capability to the user interface 708.

In some embodiments, interface(s) 708 may be configured such that a user(e.g., medical practitioner) may provide a set of control instructionsto the system (e.g., target values and/or ranges and/or otherlimitations or instructions). Optionally, interface(s) 708 may allow auser to input data from one or more sensors 705 (e.g., the results of amanual blood pressure measurement and/or results of an ultrasoundmonitor).

Optionally, the one or more user interfaces 708 may allow a user toselect a stimulation pattern (for example, from a set of stimulationpatterns stored in system 700) or impose constraints on the settingand/or selecting of a stimulation pattern.

Optionally, system 700 may comprise one or more processors 706.Processor(s) may be configured to process sensed parameters fromsensor(s) 705 and/or input data from user interface(s) 708 to select astimulation pattern for delivery by system 700. Optionally, processor(s)706 may be configured to analyze sensed parameters and extractinformation and/or formula constants to be used in the selection and/orevaluation of stimulation patterns.

One or more components of system 700 or portions of such components maybe implanted in the patient, while some components of system 700 orportions of such components may be external to the patient. When somecomponents (or component parts) are implanted and others are not,communication between the components may take place by wired and/orwireless means, essentially as known in the art. For example, some orall functions of both controller 703 and/or processor 706 may beperformed outside the body. Having some components of system 700external to the patient's body may assist in reducing the size and/orenergy requirements of an implanted device, and/or in the enhancement ofthe system's computation capabilities.

System 700 may include additional functions relating to control of heartfunction and overall cardiovascular system performance. For example,system 700 may include one or more algorithms and/or electrodes toenable biventricular pacing or resynchronization therapy to reducedyssynchrony that may be caused by ventricular stimulation. In someembodiments, system 700 may include one or more algorithms to compensatefor a possible reduction in cardiac output. Such an algorithm that maychange heart rate in order to increase cardiac output or implement othermethods known in the art for controlling cardiac output. In someembodiments, system 700 may include rate response algorithms to affectchanges in heart rate as a response to certain circumstances. Forexample, system 700 may include rate response algorithms to affectchanges in heart rate as a response to changes in level of exercise,ventilation activity, and/or oxygen consumption. In some embodiments,system 700 may include a sensor that detects activity and the algorithmmay turn off stimulation while a patient is exercising such that apatient's blood pressure is not reduced. In some embodiments, system 700may include a real-time clock. Such a clock may be used to control thetiming of the stimulation. For example, system 700 may include analgorithm that turns stimulation on and off depending upon the time ofday. This type of algorithm may be used to prevent hypotension duringthe night when a patient is sleeping.

In some embodiments, a kit including one or more components of system700 and a set of instructions for adjusting the stimulation patternbased on input relating to a patient's blood pressure may be provided.

Some embodiments may provide a system for reducing blood pressureconfigured to deliver stimulation at a rate higher than the naturalheart rate based on sensed natural heart rate or natural excitation. Forexample, the system may be configured to sense the natural excitationbetween delivery of stimulation pulses and if a natural activity issensed, the system may be configured to inhibit the delivery of thestimulation pulse to the chamber. If in a given time frame the amount ofsensed activations exceeds a threshold, the natural heart rate may beregarded as higher than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be increased, e.g., toaccommodate increased heart rate of a patient. On the other hand, if ina given time frame the amount of sensed activations is lower than athreshold (this threshold may be 0), the natural heart beat may beregarded as lower than the rate of delivery of the stimulation pulses,in which case the rate of delivery may be reduced, e.g., to avoid overexcitation of a patient's heart. To achieve this effect, according toone embodiment, a system for reducing blood pressure may include asensor for sensing an excitation rate of at least one of an atrium and aventricle of a patient's heart, a stimulation circuit configured todeliver stimulation pulses to an atrium and a ventricle, and a processorcircuit coupled to the stimulation circuit. The processor circuit may beconfigured to detect the patient's heart rate based on the sensing andoperate in an operating mode in which a stimulation pulse is provided toeach of the at least one of an atrium and a ventricle. The stimulationpulse may be delivered at a rate that is higher than the sensedexcitation rate and may be configured to stimulate the ventricle at atime between about 50 ms before and about 70 ms after stimulation of theatrium.

Some embodiments may provide a system for reducing blood pressure basedon a predicted next atrial contraction. For example, a system forreducing blood pressure may include a sensor for sensing an excitationrate of at least one of an atrium and a ventricle, a stimulation circuitconfigured to deliver a stimulation pulse to at least one of an atriumand a ventricle, and a processor circuit coupled to the stimulationcircuit. The processor circuit may be configured to operate in anoperating mode in which a timing of a next atrial excitation ispredicted based on the sensed excitation rate of the previous atrialexcitations, and at least one ventricle is stimulated at a time betweenabout 50 ms before and about 10 ms after the predicted next atrialexcitation. The predicted timing may be based on the time intervalbetween the two previous sensed atrial excitations and on a functionthat will be based on previously sensed time intervals between atrialexcitations. The function may include the change in time interval, therate of change in time intervals, and/or detection of periodicvariations in time intervals (e.g., periodic variation due tobreathing).

Optionally, a sensor for sensing the excitation rate of at least one ofan atrium and a ventricle may comprise an electrode for sensing atrialexcitation.

In a further aspect, prediction of a next atrial contraction may bebased on a function of previous sensed excitations including rate ofchange of intervals and periodic variations.

In a further aspect, the timing of the predicted next atrial excitationmay be adjusted to reflect a delay between an atrial excitation and asensing of the atrial excitation.

In a further aspect, the system may further comprise an additionalsensor for sensing a parameter relating to cardiac activity and foradjusting the time at which the ventricle is stimulated accordingly. Theparameter may be a member of a group consisting of data relating toblood pressure, blood flow, AV valve status, and wall motion of theheart or a part thereof. The additional sensor may be selected from thegroup consisting of pressure sensors, impedance sensors, ultrasoundsensors, and/or one or more audio sensors and/or one or more blood flowsensors. The additional sensor may be implantable.

Reducing Atrial Kick

Some embodiments stem from the inventors realization that blood pressurecan be reduced by causing a closure of at least one AV valve during atleast part of an atrial contraction. This will reduce, or even prevent,the contribution of the contraction of the atria to the filling of theventricles, and thus reduce cardiac filling at the end of diastole andconsequently reduce blood pressure.

In some embodiments, at least part of an atrial contraction may occuragainst a closed AV valve. For example, in some embodiments, 40% or moreof an atrial contraction may occur against a closed AV valve. In someembodiments, at least 80% of an atrial contraction may occur against aclosed AV valve. For example the contraction may start approximately 20ms or less before the contraction of the ventricle or the excitation ofthe atria may occur 20 ms or less before the excitation of theventricle. In some embodiments, 100% of an atrial contraction may occuragainst a closed AV valve, in which case ventricle excitation is timedsuch that ventricle contraction will begin before the commencement ofatrial contraction. This may include exciting the ventricle before theonset of atrial excitation. The higher the percentage is of an atrialcontraction that occurs with the AV valve closed, the more the atrialkick is reduced. Stimulation of both the atrium and the ventricle mayprovide better control of the percentage of an atrial contractionoccurring against a closed valve. Various embodiments may be implementedto cause at least part of an atrial contraction to occur against aclosed valve. For example, the AV valve may be closed 70 ms or lessafter the onset of mechanical contraction of the atrium or 40 ms or lessafter the onset of mechanical contraction of the atrium or even 5 or 10ms or less after the onset of mechanical contraction of the atrium. Insome embodiments, the AV valve may be closed before the onset ofmechanical contraction of the atrium. For example, the AV valve may beclosed within 5 ms before the onset of the mechanical contraction of theatrium. In some embodiments, the AV valve may be closed at the same timeas the onset of the mechanical contraction. In some embodiments, the AVvalve may be closed after the onset of the mechanical contraction of theatrium. For example, the AV valve may be closed within 5 ms after theonset of mechanical contraction of the atrium.

In some embodiments, the onset of a contraction of a chamber may besensed and a stimulation pulse may be timed relative to the sensed onsetof a contraction. The onset of contraction in a chamber is the start ofactive generation of contractile force in the chamber. The onset ofcontraction can be sensed by a rapid change in pressure that is notrelated to the flow of blood into the chamber. The onset of contractionmay also be sensed by measuring the movement of the walls of a cardiacchamber or measuring the reduction in volume of a chamber using anultrasound. These methods of sensing the onset of a contraction may havea delay between the actual onset of the contraction and the sensing ofan onset of contraction.

In some embodiments, the AV valve may be closed after the onset ofcontraction of at least one atrium. For example, the AV valve may beclosed about 0 ms to about 70 ms after the onset of contraction of atleast one atrium. In some embodiments, the AV valve may be closed about0 ms to about 40 ms after the onset of contraction of at least oneatrium. In some embodiments, the AV valve may be closed about 0 ms toabout 10 ms after the onset of contraction of at least one atrium. Insome embodiments, the AV valve may be closed about 0 ms to about 5 msafter the onset of contraction of at least one atrium.

Typically, an atrial contraction may begin about 40 ms to about 100 msafter the onset of atrial excitation. In some embodiments, the AV valvemay be closed after the onset of atrial excitation. For example, the AVvalve may be closed about 40 ms to about 170 ms after the onset ofatrial excitation. For example, the AV valve may be closed about 40 msto about 110 ms after the onset of atrial excitation. In anotherembodiment, the AV valve may be closed about 40 ms to about 80 ms afterthe onset of atrial excitation. For example, the AV valve may be closedabout 40 ms to about 75 ms after the onset of atrial excitation. Forexample, the AV valve may be closed about 40 ms to about 50 ms after theonset of atrial excitation.

In some embodiments, the onset of excitation in a chamber may be sensedand a stimulation pulse may be timed relative to the sensed onset ofexcitation. The onset of excitation is the initiation of a propagatingaction potential through a chamber. The onset of excitation may besensed by sensing the local electrical activity of a chamber using asensing electrode connected to an amplifier. The onset of excitation canalso be detected by electrocardiography.

In some embodiments, methods of sensing the onset of excitation may havea delay between the actual onset of the excitation and the sensing of anonset of excitation. The timing of a sensed atrial excitation may bedetermined by taking into account the delay between actual onset ofexcitation and the sensing thereof. For example, if a sensing delay isestimated to be 20-40 ms, and stimulation pulses are to be delivered0-70 ms after onset of atrial excitation, a system may be set to deliverpulses between 40 ms before the next anticipated sensing event to 30 msafter the next anticipated sensing event or 30 ms after the next sensingevent. Likewise, if the stimulation pulses are to be delivered to theventricle 0-50 ms before onset of atrial excitation, assuming the same20-40 ms sensing delay, a system may be set to deliver pulses between 40ms before the next anticipated sensing event to 90 ms before the nextanticipated sensing event. Sensing delays may be due to one or more of adistance between the site of onset of excitation and a sensingelectrode, the level of the electrical signal, characteristics of thesensing circuit, and the threshold set of a sensing event. The delay mayinclude, for example, the duration of the signal propagation from theorigin of excitation to the electrode location, the duration related tothe frequency response of the sensing circuit, and/or the durationnecessary for the signal propagation energy to reach a level detectableby a sensing circuit. The delay may be significant and can range, forexample, between about 5 ms to about 100 ms. One approach for estimatingthe delay is to use the time difference between an AV delay measuredwhen both atrium and ventricle are sensed and the AV delay when theatrium is paced and the ventricle is sensed. Other approaches may usecalculation of the amplifier response time based on the set threshold,signal strength, and frequency content. Other approaches may includemodifying the delay used with atrial sensing until the effect on bloodpressure is the same as the effect obtained by pacing both atrium andventricle with the desired AV delay.

In some embodiments, the AV valve may be closed before the onset ofexcitation or contraction of at least one atrium. For example, the AVvalve may be closed within about 0 ms to about 5 ms before the onset ofexcitation or contraction of at least one atrium. In some embodiments,the AV valve may be closed at the same time as the onset of excitationor contraction of at least one atrium.

In some embodiments, direct mechanical control of AV valve closure maybe performed. In such embodiments, a mechanical device or a portionthereof may be implanted in the patient, and operated to cause theclosing of a valve between the atrium and ventricle. For example, anartificial valve may be implanted in the patient's heart and operated toclose mechanically in accordance with some embodiments. In suchembodiments, instead of or in addition to providing a stimulationpattern, the aforementioned closure of the AV valves may be accomplishedby controlling the functioning of the implanted valve.

In some embodiments, a shortened or even negative time interval betweenthe onset of atrial excitation and ventricular excitation is employed toreduce cardiac filling, thereby reducing blood pressure. As used herein,a negative time interval between the onsets of atrial excitation andventricular excitation means that in a single cardiac cycle, the onsetof excitation for the at least one ventricle occurs before the onset ofatrial excitation. In this case, atrial contraction may take place, atleast partially, against a closed AV valve, since the generated pressurein the ventricles may be greater than the pressure in the atria. A shorttime after the initiation of ventricular contraction, the pressure inthe ventricles may exceed the pressure in the atria and may result inthe passive closure of the valve. This closure of the valve may reduceor even obliterate the atrial kick and, in turn, reduce ventricularfilling. Consequently, the force of ventricular contraction may bereduced and blood pressure may drop.

The time between the start of excitation and the start of the mechanicalcontraction in each cardiac chamber is not fixed. Thus, the timing ofexcitation does not guarantee the same effect on the timing betweencontractions. However, in some embodiments, the timing betweenexcitations is used as a frame of reference for practical reasons. Theultimate purpose of controlling the timing of excitation is to controlthe timing of a contraction.

In some embodiments, a shortened or even negative time interval betweenthe onset of atrial contraction and ventricular contraction may beemployed to reduce cardiac filling, thereby reducing blood pressure. Inthis case, better control over the contribution of the atria may beobtained since the start of the contraction of the ventricle will resultwith the closure of the valve.

In some embodiments, 40% or more of an atrial contraction may occurduring ventricular systole. For example, the atrial contraction maystart approximately 60 ms or less before the contraction of theventricle, or the excitation of the atria may occur 60 ms or less beforethe excitation of the ventricle. In some embodiments 80% or more of anatrial contraction may occur during ventricular systole. For example,the contraction may start approximately 20 ms or less before thecontraction of the ventricle, or the excitation of the atria may occur20 ms or less before the excitation of the ventricle. In someembodiments, 100% of an atrial contraction may occur during ventricularsystole, in which case ventricle excitation is timed such that ventriclecontraction will begin before the commencement of atrial contraction.This may include exciting the ventricle before the onset of atrialexcitation.

Some embodiments provide a method for causing the contraction of atleast one ventricle of a heart, such that the at least one ventriclecontracts during or before the contraction of the corresponding atrium.One way to achieve this goal is by exciting the ventricle at a point intime between about 50 ms before to about 70 ms after the onset ofexcitation of the corresponding atrium. In some embodiments, the timeinterval between the onset of excitation of at least one ventricle andthe onset of excitation of the corresponding atrium may be zero. Inother words, the onset of excitation for the at least one ventricle mayoccur at the same time as the onset of excitation of the correspondingatrium. In some embodiments, the onset of excitation of the ventriclemay occur between about 0 ms to about 50 ms before the onset of atrialexcitation. In some embodiments, the onset of excitation of theventricle may occur at least 2 ms before to at least 2 ms after theonset of excitation of the at least one atrium. In some embodiments, theonset of excitation of the ventricle may occur at least 10 ms before toat least 10 ms after the onset of excitation of the at least one atrium.In some embodiments, the onset of excitation of the ventricle may occurat least 20 ms before to at least 20 ms after the onset of excitation ofthe at least one atrium. In some embodiments, the onset of excitation ofthe ventricle may occur at least 40 ms before to at least 40 ms afterthe onset of excitation of the at least one atrium.

In some embodiments, a method may comprise delivering a stimulationpulse from a stimulation circuit to at least one of an atrium and aventricle, and operating a processor circuit coupled to the stimulationcircuit to operate in an operating mode in which a ventricle isstimulated to cause ventricular excitation to commence between about 0ms and about 50 ms before the onset of atrial excitation in at least oneatrium, thereby reducing the ventricular filling volume from thepretreatment ventricular filling volume and reducing the patient's bloodpressure from the pretreatment blood pressure. In such embodiments,atrial excitation may be sensed to determine the onset of atrialexcitation. The time interval between the onset of atrial excitation andthe moment that atrial excitation is sensed may be known and used tocalculate the timing of the onset of atrial excitation. For example, ifit is known that atrial excitation is sensed 20 ms after the onset ofatrial excitation and the ventricle is to be stimulated 40 ms before theonset of atrial excitation, then the ventricle is to be stimulated 60 msbefore the anticipated sensing of atrial excitation. In otherembodiments, the method may comprise operating a processor circuitcoupled to the stimulation circuit to operate in an operating mode inwhich an atrium is stimulated to cause atrial excitation to commencebetween about 0 ms and about 50 ms after the onset of ventricularexcitation in at least one ventricle, thereby reducing the ventricularfilling volume from the pretreatment ventricular filling volume andreducing the patient's blood pressure from the pretreatment bloodpressure. For example, the processor circuit may be configured tooperate in an operating mode in which one or more excitatory pulses aredelivered to an atrium between about 0 ms and about 50 ms after one ormore excitatory pulses are provided to the patient's ventricle. In suchembodiments, the pacing may be timed without relying on sensing atrialexcitation. Optionally, in such embodiments, atrial excitation is sensedin order to confirm that one or more excitatory pulses are delivered toan atrium before a natural excitation takes place. Optionally, atrialexcitation is set to commence between about 0 ms and about 50 ms afterthe onset of ventricular excitation when the intrinsic atrial excitationrate is lower than the intrinsic ventricular excitation rate.

In some embodiments, a device may comprise a stimulation circuitconfigured to deliver a stimulation pulse to at least one of an atriumand a ventricle. The device may comprise a processor circuit coupled tothe stimulation circuit. In some embodiments, the processor circuit maybe configured to operate in an operating mode in which a ventricle isstimulated to cause ventricular excitation to commence between about 0ms and about 50 ms before the onset of atrial excitation in at least oneatrium, thereby reducing the ventricular filling volume from thepretreatment ventricular filling volume and reducing the patient's bloodpressure from the pretreatment blood pressure. In such embodiments,atrial excitation may be sensed to determine the onset of atrialexcitation. The time interval between the onset of atrial excitation andthe moment that atrial excitation is sensed may be known and used tocalculate the timing of the onset of atrial excitation. For example, ifit is known or estimated that atrial excitation is sensed 20 ms afterthe onset of atrial excitation and the ventricle is to be stimulated 40ms before the onset of atrial excitation, then the ventricle is to bestimulated 60 ms before the anticipated sensing of atrial excitation. Inother embodiments, the processor circuit may be configured to operate inan operating mode in which an atrium is stimulated to cause atrialexcitation to commence between about 0 ms and about 50 ms after theonset of ventricular excitation in at least one ventricle, therebyreducing the ventricular filling volume from the pretreatmentventricular filling volume and reducing the patient's blood pressurefrom the pretreatment blood pressure. For example, the processor circuitmay be configured to operate in an operating mode in which one or moreexcitatory pulses are delivered to an atrium between about 0 ms andabout 50 ms after one or more excitatory pulses are provided to thepatient's ventricle. In such embodiments, the pacing may be timedwithout relying on sensing atrial excitation. Optionally, in suchembodiments atrial excitation is sensed in order to confirm that one ormore excitatory pulses are delivered to an atrium before a naturalexcitation takes place. Optionally, atrial excitation is set to commencebetween about 0 ms and about 50 ms after the onset of ventricularexcitation when the intrinsic atrial excitation rate is lower than theintrinsic ventricular excitation rate.

FIGS. 10A and 10B depict a healthy anesthetized canine heart, showing anelectrocardiogram (ECG), left ventricle pressure (LVP) and arterial(blood) pressure (AP) traced over a period of time. In FIG. 10A, beforepoint 101, the heart was allowed to beat naturally, and the ECG, LVP,and AP were traced. At point 101, ventricular pacing commenced. Theventricle was paced 2 ms after the onset of atrial excitation. Thispacing caused an immediate change in the ECG, which was concomitant witha reduction of both LVP and AP. The pacing continued at a 2 ms timeinterval between the onset of atrial contractions and the onset ofventricular pacing until point 103 in FIG. 10B, where pacing ceased. Asseen, immediately upon cessation of pacing, the ECG, LVP, and BP allreturned essentially to the same values as before pacing.

FIGS. 11A and 11B show a hypertensive canine heart under a naturalheartbeat (FIG. 11A) and when paced at a time interval of 2 ms betweenthe onset of atrial contractions and ventricular pacing (FIG. 11B). Eachof these figures shows traces of an ECG, right ventricular pressure(RVP), a magnified portion of the RVP, and right atrial pressure (RAP)of the heart.

In FIG. 11A, the P wave and QRS of the natural heartbeat are clearlyseen. An increase in atrial pressure is seen following the P wave as aresult of atrial contraction. In the RVP trace, a sharp increase in RVPis seen following a QRS complex on the ECG. This is a manifestation ofventricular contraction. When observed at a higher magnification, thissharp increase in RVP is preceded by an earlier, smaller increase inRVP, which coincides with atrial contraction and a reduction in atrialpressure and is a result of blood emptying from the atrium into thechamber. This is the atrial kick. In FIG. 11B, where pacing is at a timeinterval of 2 ms, the P wave is essentially unnoticeable on the ECG, andan artifact of the electrical stimulator is discernible. The atrial kickin this case is not visible on the magnified trace of right ventricularpressure because the atrial contraction occurred at the same time oreven a little after the start of ventricular contraction.

In FIG. 12, a hypertensive canine heart was paced either at a timeinterval of 60 ms between the pacing of the atria and the pacing of theventricle (trace portions 105 and 107) or a time interval 120 ms ofbetween atrial and ventricular pacing (trace portion 109). The traceshows the ECG of the heart, left ventricular pressure (LVP), rightventricular pressure (RVP), a magnification of RVP, and right atrialpressure (RAP). As seen in trace portions of RVP magnified correspondingwith trace portions 105 and 107, the atrial kick during pacing at the 60ms time interval is very slight and the contraction of the ventriclebegins slightly after the peak of atrial contraction. In this case thecontribution of atrial kick to ventricular filling is markedly reducedbut not totally eliminated and, on the other end, the peak of atrialcontraction does not occur against a closed valve and atrial stretchdoes not increase. During pacing at a time interval of 120 ms, theatrial kick is clearly seen (portion 109 in trace RVP magnified), butthe start of the ventricular contraction and the closure of the AV valveoccur before the completion of atrial contraction, thereby slightlyreducing the contribution of the atrial kick to ventricular filling.

In FIG. 16, the heart of a hypertensive patient was paced with differentAV delays. This example shows the results obtained by pacing in both anatrium and a corresponding ventricle versus pacing only the ventriclebased on the sensed pulses in the atrium. During interval d-d′, atrialpulses were sensed and ventricular pulses were paced with an AV delay of2 ms. During interval e-e′, the atrium and ventricle were both pacedwith an AV delay of 2 ms. During interval f-f′, the atrium and theventricle were both paced with an AV delay of 40 ms. During intervalg-g′, the atrium and the ventricle were both paced with an AV delay of20 ms. During interval h-h′, the atrium and the ventricle were bothpaced with an AV delay of 80 ms. As shown in this example, whencomparing interval d-d′ with interval e-e′, the blood pressure isreduced more when the atrium is paced during interval e-e′ than whenatrial activity was just sensed. As also shown in this example, whencomparing interval e-e′, interval f-f′, interval g-g′, and intervalh-h′, the shorter AV delays caused more of a reduction in blood pressurethan the longer ones. For example, interval g-g′ (20 ms AV-delay) showsa higher blood pressure than interval e-e′ (2 ms AV-delay). As shownfrom the results of this example, the changes in blood pressure may becaused at least partially by the different AV delays, which result indifferent percentages of atrial contraction against a closed valve.

Exemplary Embodiments of Methods for Reducing Atrial Kick

An exemplary method 40 for reducing blood pressure is depictedschematically in FIG. 13. Method 40 may be performed by device 50 ofFIG. 14, described below. Accordingly, device 50 may be configured toperform any or all steps of method 40. Similarly, method 40 may includeany steps device 50 is configured to perform. For example, method 40 mayinclude any of the functions discussed above with respect to device 50.Method 40 may include any steps from method 600. Similarly, method 600may include any steps from method 40. Method 40 may include any stepsthat system 700 may be configured to perform. System 700 may beconfigured to perform any or all steps of method 40.

In some embodiments, method 40 may include a step 41 of atrialexcitation. In some embodiments, step 41 includes sensing an atrialexcitation. For example, step 41 may include sensing an intrinsic atrialexcitation. In some embodiments, step 41 includes triggering atrialexcitation. Method 40 may include a step 42 in which a time interval isapplied. Method 40 may include a step 43 of triggering AV valve closure.In some embodiments, step 43 may be performed by applying an excitatorycurrent to the at least one ventricle and/or by actuating an artificialvalve between the at least one atrium and the corresponding ventricle(s)to close. In some embodiments, step 41, step 42, and step 43 may berepeated as depicted by a return arrow leading back to step 41 from step43. In some embodiments, an excitatory current may be applied to bothventricles, at the same time or in sequence. In some embodiments, whereboth ventricles are paced in sequence, the time interval may be measuredbetween the onset of excitation of at least one atrium (e.g., the rightatrium) and the onset of excitation of the corresponding ventricle to bepaced (e.g., the right ventricle). In some embodiments, where the timeinterval is set to be zero or negative, step 43 may be performed beforeor at the same time as step 41. In some embodiments, the time intervalmay be measured in milliseconds.

Optionally, contraction of the atrium and the ventricle may be caused bycontrolling both contractions (e.g. by controlling the excitationsleading to the contractions). Optionally, the onset of excitation of theatrium is sensed, which sensing triggers the closing of a valve at theprescribed timing interval. Optionally, both atria are paced. In someembodiments, where both AV valves are closed in sequence (e.g., as bothventricles are paced in sequence), the timing interval is measured fromthe onset of excitation of the first atrium to be paced and the onset ofthe valve closing or the onset of excitation of at least one ventricle.Optionally the timing of an excitation (e.g. the onset of excitation) ofone or more chambers is estimated, for example based on the timing inone or more preceding heart cycles, and one or more excitation stimuliare delivered to the same and/or to a different chamber at a desiredtime interval before and/or after the estimated timing.

In some embodiments, method 40 may be repeated for every heartbeat. Insome embodiments, method 40 may be performed intermittently. Forexample, the method may be applied once every few heartbeats.Alternatively, method 40 may be applied for a few heartbeats, stoppedfor one or more heartbeats, and then applied again. For example, method40 may be applied for 5 to 15 heartbeats, stopped for 2 to 5 heartbeats,and then resumed again. In some embodiments, the pattern ofapplication/avoiding application may be more complex and may beoptionally based on a predefined algorithm. For example, an algorithmmay adjust parameters of stimulation rather than simply stop and startstimulation. Application of method 40 in some embodiments reducesventricle filling between heartbeats thereby potentially reducing theejection profile. As used herein, the ejection profile of a heart is thetotal amount of blood pumped by the heart in a given period of time. Insome embodiments, an intermittent application of method 40 may beapplied to counteract a reduction in the ejection profile of the heart.

In some embodiments, the time interval applied in step 42 may beselected based on feedback. In such cases, method 40 may include step 44of sensing a feedback parameter from one or more of the heart chambers,any portion thereof, and/or the body of the patient. For example,feedback information may be obtained by monitoring directly orindirectly one or more of the atrial kick, blood pressure (e.g., at anartery), ventricular pressure, and/or atrial pressure. In someembodiments, feedback information may additionally or alternativelyinclude the degree of overlap between the time when the atrium contractsand the time when the AV valve is closed and/or the time when theventricle contracts. For example, an ultrasound sensor may be used todetect cardiac activity, for example, by ultrasound imaging of cardiacactivity or by creating an echocardiogram (ECHO). In some embodiments,step 44 may include using an ultrasound sensor to detect the flow ofblood (e.g., the velocity of flow) and/or cardiac tissue movement at anyarbitrary point using pulsed or continuous wave Doppler ultrasound.Optionally, step 44 may include using an ultrasound sensor to detect anA wave corresponding to the contraction of the left atrium and the flowof blood to the left ventricle.

Method may include a step 45 of adjusting the time interval from step 42based on the feedback information from step 44. For example, step 45 mayinclude adjusting the time interval based on a sensed blood pressure. Asshown by the arrow directed from step 45 to step 41 in FIG. 13, step 41,step 42, step 43, and/or step 44 may be repeated after performing step45. In some embodiments, the time interval may be initially set at afirst value during step 41 and, based on feedback sensing performedduring step 44, the time interval may be reduced or increased duringstep 45 until the feedback value is within a given range (or above orbelow a given value). For example, the time interval may be adjusteduntil such time that systolic blood pressure is above 100 mmHg and/orbelow 140 mmHg and/or diastolic blood pressure is below 90 mmHg and/orabove 60 mmHg.

In some embodiments, step 44 and step 45 may be performed duringoperation of method 40 for every application of step 43 (e.g.,application of a ventricular pacing stimulus). In some embodiments,alternatively or additionally, step 44 and step 45 may be performed uponproviding a device to a patient (e.g., by implantation of the device)according to one or more embodiments. The adjusting steps may berepeated periodically (for example by a care taker during a checkup)and/or intermittently (for example once an hour or once every fewapplications of a ventricular pacing stimulus). In some embodiments,step 45 may be performed when feedback information indicates that one ormore sensed parameters exceed a preset range for a period of time thatexceeds a predefined period.

The steps of method 40 may be performed in any order. For example, thesteps may be performed in the order indicated by the arrows shown inFIG. 13. In another embodiment, step 42 may be performed before step 41.

The timing of atrial contraction, atrial excitation, ventricularcontraction, closing and/or opening of the AV valve(s), and/or the flowor lack thereof of blood from one or more atria to the respectiveventricle(s) and/or blood pressure may be detected by any method knownin the art and may be used as feedback control. In some embodiments, theonset of excitation may be used as a trigger for the delivery of anexcitatory stimulus to one or more ventricles. The sensed informationmay be additionally or alternatively be used in the adjusting of atiming interval of the device.

Optionally, feedback parameters may allow responding to conditions thatrequire additional throughput from the heart, and rather than adjust thetiming interval they may be used to automatically stop the causing ofvalve closing at a shortened timing interval. For example, the feedbackparameters may lead to an adjustment during exercise. In this example, aheart rate sensor may be used to provide feedback information on theheart rate of the patient. If the heart rate is above a given thresholdthe feedback may be used to cause the device to stop. The device may beactivated again based on sensed feedback information, for example, whenthe heart rate is below a given threshold and/or after a predeterminedperiod has passed.

Embodiments of Devices for Reducing Blood Pressure

Attention is now drawn to FIG. 14, which schematically depicts anexemplary device 50 according to an embodiment. Device 50 may beconstructed and have components similar to a cardiac pacemakeressentially as known in the art with some modifications as discussedherein. Optionally, the device is implantable. Optionally, the devicecomprises components that may provide additional and/or alternativeelectrical treatments of the heart (e.g., defibrillation). Device 50 maybe configured for implantation in the body of a patient essentially asis known in the art for implantable pacemakers, optionally with somemodifications as discussed herein. Device 50 may include any componentsof system 700 and system 700 may include any components of device 50.

Device 50 may include a biocompatible body 51, one or more controllers52, a power source 53, and a telemetry unit 56. Body 51 may comprise ahousing for encasing a plurality of components of the device.Controller(s) 52 may be configured to control the operation of thedevice. For example, controller(s) 52 may control the delivery ofstimulation pulses. In some embodiments, power source 53 may include abattery. For example, power source 53 may include a rechargeablebattery. In some embodiments, power source 53 may include a battery thatis rechargeable by induction. In some embodiments, telemetry unit 56 maybe configured to communicate with one or more other units and/orcomponents. For example, telemetry unit 56 may be configured tocommunicate with an external programmer and/or a receiving unit forreceiving data recorded on device 50 during operation.

In some embodiments, device 50 may be configured to be attached to oneor more electrodes and/or sensors. The electrodes and/or sensors may beintegrated in device 50, attached thereto, and/or connectable therewith.In some embodiments, the electrodes may include ventricular electrode(s)561 configured to pace at least one ventricle. Additionally oralternatively, the device may be connected, optionally via wires orwirelessly, to at least one implanted artificial valve 562.Additionally, device 50 may comprise one or more atrial electrode(s) 57for pacing one or more atria, and/or one or more atrial sensors 58 forsensing the onset of atrial excitation, and/or one or more sensors 59for providing other feedback parameters.

In some embodiments, sensor(s) 59 may comprise one or more pressuresensors, electrical sensors (e.g., ECG monitoring), flow sensors, heartrate sensors, activity sensors, and/or volume sensors. Sensor(s) 59 mayinclude mechanical sensors and/or electronic sensors (e.g., ultrasoundsensors, electrodes, and/or RF transceivers). In some embodiments,sensor(s) 59 may communicate with device 50 via telemetry.

In some embodiments, ventricular electrode(s) 561 and/or atrialelectrode(s) 57 may be standard pacing electrodes. Ventricularelectrode(s) 561 may be positioned relative to the heart at positions asknown in the art for ventricular pacing. For example, ventricularelectrode(s) may be placed in and/or near one or more of the ventricles.In some embodiments, atrial electrode(s) 57 may be placed in and/or nearone or more of the atria. In some embodiments, atrial electrode(s) 57may be attached to the one or more atria at one or more positionsselected to provide early detection of atrial excitation ordepolarization. For example, in some embodiments, atrial electrode(s) 57may be attached to the right atrium near the site of the sinoatrial (SA)node.

One position of ventricular electrode(s) 561 may be such that pacing mayreduce or minimize the prolongation of QRS when the heart is paced, toreduce or even minimize dyssynchrony. In some embodiments, this positionis on the ventricular septum near the Bundle of His. Ventricularelectrode(s) 561 may additionally or alternatively be placed on theepicardium of the heart or in coronary veins. More than one electrodecan be placed on the ventricles to provide biventricular pacing,optionally to reduce dyssynchrony.

Device 50 may include a pulse generator, or stimulation circuit,configured to deliver a stimulation pulse to at least one cardiacchamber. The pulse generator, or stimulation circuit, may include someor all standard capabilities of a conventional pacemaker. Controller 52may be configured to control the pulse generator, or stimulationcircuit. Atrial sensor(s) 58 (and optionally other electrode sensorsconfigured to sense other heart chambers) may be connected to device 50via specific circuits that will amplify the electrical activity of theheart and allow sampling and detection of the activation of the specificchamber. Other circuits may be configured to deliver stimulation to aspecific electrode to pace the heart, creating propagating electricalactivation.

In some embodiments, one or more additional sensors 59 may be placed inand/or on one or more of the atria and/or in and/or on one or more ofthe ventricles and/or in and/or on one or more other locations thatmight optionally be adjacent the heart. For example, one or more sensorsmay be placed on and/or in vena cava and/or on one or more arteriesand/or within one or more cardiac chambers. These sensors may measurepressure, or other indicators, such as, for example, impedance and/orflow.

In some embodiments, controller 52 may comprise or be a microprocessorpowered by power source 53. In some embodiments, device 50 may comprisea clock 54, for example, generated by a crystal. Device 50 may comprisean internal memory 55 and/or be connected to external memory. Forexample, device may connect to an external memory via telemetry unit 56.In some embodiments, telemetry unit 56 may be configured to allowcommunication with external devices such as a programmer and/or one ormore of sensors 59. Any and all feedback information and/or a log ofdevice operation may be stored in internal memory 55 and/or relayed bytelemetry unit 56 to an external memory unit.

In some embodiments, controller 52 may operate in accordance with atleast one embodiment of a method described herein.

In some embodiments, device 50 may comprise one or more sensors forsensing one or more feedback parameters to control the application ofthe AV delay and/or its magnitude.

Embodiments of Artificial Valves

Additionally or alternatively, device 50 may be configured to directlycontrol the operation of at least one implanted artificial valve 562.Attention is now drawn to FIG. 15, which schematically depicts anartificial valve 60 according to an embodiment of the invention. Valve60 as depicted in the example is a bi-leaflet, essentially as known inthe art for artificial valves. While the following example relates to abi-leaflet valve it is appreciated that embodiments may be implementedin other artificial valves, for example, caged ball valves and discvalves as well.

As shown in FIG. 15, valve 60 may comprise a ring 61 for suturing thevalve in place when implanted in a heart of a patient. Valve 60 mayinclude two semicircular leaflets 62 that rotate about struts 63attached to ring 61. In this schematic representation, other devicecomponents are schematically depicted as body 64, which corresponds tobody 51 as shown in FIG. 14. Body 64 may receive feedback informationfrom heart 65, in which valve 60 is implanted.

Valve 60 differs from conventional artificial valves in that its closuremay be directly controlled by device 50. Valve 60 may comprise amechanism (for example, a coil or a hydraulic mechanism) that isconfigured to actively cause closure of the valve (for example, byrotating struts 63 or by inflating a portion of the one or more ofleaflets 62). The mechanism may later be brought back to a relaxedposition to allow opening of the valve and to allow its repeated closingas needed. The relaxation may be performed at a predetermined time afterclosing. Additionally or alternatively, relaxation may be affected inresponse to a sensor reading ventricular activity (e.g., a pressuresensor). Control over valve 60 may be operated wirelessly (using atelemetry unit associated with the valve) or by wired communication withcomponents in body 64. In some embodiments, valve 60 may be a valveconfigured to be opened and closed independent of fluid pressure actingon the valve. For example, valve 60 may be a ball valve.

Effects of Embodiments for Reducing Blood Pressure

Overall, some embodiments of the disclosed methods and systems providedifferent approaches to reducing the filling of at least one ventricle,consequently reducing blood pressure. Unlike previous mechanical methodsfor reducing blood pressure, some embodiments described herein mayachieve this goal without increasing pressure within the at least onecorresponding atrium. Without an increase in atrial pressure to triggerthe secretion of atrial natriuretic hormone, or atrial natriureticpeptide, the reduction of blood pressure can be mechanically controlled.The disclosed embodiments may prevent an unwanted effect on heart rateand may reduce the likelihood of canon atrial waves.

Some of the disclosed embodiments may reduce atrial kick while alsoincreasing atrial stretch, causing the release of atrial natriureticpeptide. For example, disclosed embodiments may comprise a methodincluding a step of stimulating a heart to cause an atrium thereof tocontract while a heart valve associated with the atrium is closed suchthat the contraction distends the atrium. Reducing atrial kick andcausing the release of atrial natriuretic peptide at the same time mayhave a synergistic effect on lowering blood pressure. In someembodiments, controlling the timing of valve closure relative to atrialcontraction may control the amount one or more atria stretches.

Unlike previous pharmaceutical or mechanical methods for reducing bloodpressure, some of the disclosed embodiments achieve the goal of reducingblood pressure immediately. For example, a reduction in blood pressuremay occur within 1-3 sec or within 1, 3, or 5 heartbeats of theapplication of electricity and the blood pressure may reach a minimalblood pressure value within less than 5 heartbeats from the beginning ofstimulation.

Examples discussed above strike a balance between mechanical treatment,neuronal feedback, and the natural release of hormones that causeadaptation. The mechanical treatment and the natural release of hormonesmay be additive or even synergistic mechanisms. The hormonal releaseaffects the cardiovascular system while the mechanical treatment affectsthe heart itself. Intermittently delivering the mechanical treatment toreduce blood pressure may affect both the neuronal and hormonal feedbackcontrolling the cardiovascular system and reduce adaptation.

The headings used in this specification are only meant to aid inorganization and do not define any terms.

The present disclosure is related to the following applications, all ofwhich are incorporated by reference in their entirety:

-   -   U.S. Patent Application Publication Number 2012/0215272 to Levin        et al., published on Aug. 23, 2012;    -   U.S. Patent Application Publication Number 2011/0172731 to Levin        et al., published on Jul. 14, 2011;    -   U.S. patent application Ser. No. 13/688,978 to Levin et al.,        filed on Nov. 29, 2012; and    -   U.S. Patent Application Publication Number 2012/0041502 to        Schwartz et al., published on Feb. 16, 2012.

While various embodiments of the invention have been described, thedescription is intended to be exemplary, rather than limiting and itwill be apparent to those of ordinary skill in the art that many moreembodiments and implementations are possible that are within the scopeof the invention. Accordingly, the invention is not to be restrictedexcept in light of the attached claims and their equivalents. Also,various modifications and changes may be made within the scope of theattached claims.

What is claimed is:
 1. A method, carried out with an implanted heartmuscle stimulator associated with a heart of a patient, for treating ablood pressure disorder in the patient, the patient having apretreatment blood pressure, the method comprising: determining a futureanticipated contraction of an atrium of the heart; delivering, to aventricle of the heart associated with the atrium, one or morestimulation pulses a pacing time interval before the future anticipatedcontraction of the atrium, such that the ventricle begins contractingbefore the future anticipated contraction of the atrium begins; andreducing blood pressure of the patient to below the pretreatment bloodpressure by at least one of reduced ventricular filling or increasedatrial stretch.
 2. The method of claim 1, further comprising deliveringto the atrium one or more stimulation pulses after the pacing timeinterval to cause the future anticipated contraction of the atrium. 3.The method of claim 2, further comprising sensing atrial excitation toconfirm that the one or more stimulation pulses delivered to the atriumare delivered before a natural excitation of the atrium takes place. 4.The method of claim 1, further comprising allowing the futureanticipated contraction of the atrium to occur naturally withoutstimulation.
 5. The method of claim 1, further comprising: sensing anatural activity rate of the atrium; and setting the pacing timeinterval preceding the future anticipated contraction of the atriumbased on the sensed natural activity rate.
 6. The method of claim 1,further comprising: sensing atrial excitation to determine onset ofatrial excitation; determining a sensing delay interval as a durationfrom the onset of atrial excitation to when the atrial excitation issensed; and determining, based on the sensing delay interval, the pacingtime interval preceding the future anticipated contraction of theatrium.
 7. The method of claim 6, wherein estimating the sensing delayinterval comprises modifying the sensing delay interval until aresulting effect on blood pressure is equal to an effect obtained bypacing both the atrium and the ventricle with a desired atrioventriculardelay.
 8. The method of claim 1, further comprising determining thepacing time interval by accounting for a relation between mechanicalcontraction and electrical excitation of the ventricle.
 9. The method ofclaim 1, wherein the pacing time interval is between about 0 ms andabout 50 ms.
 10. The method of claim 1, wherein the atrium contracts atleast partially against a closed atrioventricular valve between theatrium and the ventricle.
 11. The method of claim 10, further comprisingreducing atrial kick by closure of the closed atrioventricular valve,thereby causing the reduced ventricular filling.
 12. The method of claim1, wherein 100% of the future anticipated contraction of the atriumoccurs during ventricular systole of the ventricle.
 13. The method ofclaim 1, further comprising setting the pacing time interval betweenabout 0 ms and about 50 ms when an intrinsic atrial excitation rate ofthe atrium is lower than an intrinsic ventricular excitation rate of theventricle.
 14. The method of claim 1, further comprising: sensing atleast one cardiac activity parameter comprising at least one of bloodpressure, blood flow, atrioventricular valve status, or wall motion ofthe heart or a part thereof; and adjusting the pacing time intervalbased on the sensed at least one cardiac activity parameter.
 15. Amethod for reducing blood pressure of a patient, the method comprising:delivering stimulation pulses to an atrium and a ventricle of a heart ofthe patient at a first delivery rate expected to be higher than anatural heart rate of the heart; sensing whether a natural excitationoccurs between delivery of the stimulation pulses; when the naturalexcitation occurs, inhibiting delivery of next stimulation pulses to theatrium and the ventricle; when an amount of sensed natural excitationsexceeds a predetermined higher threshold over a given time frame,identifying the natural heart rate as higher than the first deliveryrate, and increasing the first delivery rate to a second delivery ratethat is higher than the natural heart rate; and when an amount of sensednatural excitations is lower than a predetermined lower threshold over agiven time frame, decreasing the first delivery rate to a third deliveryrate to avoid over-excitation of the heart.
 16. The method of claim 15,further comprising sensing the natural heart rate.
 17. The method ofclaim 16, wherein the first delivery rate is higher than the sensednatural heart rate of the heart, and wherein delivering the stimulationpulses to the atrium and the ventricle comprises stimulating theventricle at a time between about 50 ms before and about 70 ms afterstimulation of the atrium.
 18. The method of claim 15, whereindelivering the stimulation pulses causes ventricular excitation before astimulation pulse is delivered to the atrium, and wherein thestimulation pulse delivered to the atrium is delivered at a time that isearlier than a next anticipated natural onset of atrial excitation. 19.The method of claim 15, further comprising reducing blood pressure ofthe patient to below a pretreatment blood pressure by at least one ofreduced ventricular filling or increased atrial stretch.
 20. A systemfor treating a blood pressure disorder in a patient, the patient havinga pretreatment blood pressure, the system comprising: a stimulationcircuit configured to deliver a stimulation pulse to at least onecardiac chamber of a heart of the patient; and at least one controllerconfigured to execute delivery to a ventricle of the heart one or morestimulation pulses a pacing time interval before a future anticipatedcontraction of an atrium associated with the ventricle, such that theventricle begins contracting before the future anticipated contractionof the atrium begins, thereby reducing blood pressure of the patient tobelow the pretreatment blood pressure by at least one of reducedventricular filling or increased atrial stretch.
 21. The system of claim20, wherein the at least one controller is further configured to deliverto the atrium one or more stimulation pulses after the pacing timeinterval to cause the future anticipated contraction of the atrium. 22.The system of claim 20, further comprising: a first sensor that sensesan excitation rate of at least one of the atrium or the ventricle; and asecond sensor that senses a parameter relating to cardiac activity,wherein the least one controller adjusts the pacing time interval basedon the sensed parameter.
 23. The system of claim 22, wherein theparameter comprises at least one of blood pressure, blood flow,atrioventricular valve status, or wall motion of the heart or a partthereof.
 24. The system of claim 22, wherein the second sensor comprisesat least one of a pressure sensor, an impedance sensor, an ultrasoundsensor, an audio sensor, or a blood flow sensor.